Aryl-phenyl-sulfonamido-cycloalkyl compounds and their use

ABSTRACT

The present invention pertains generally to the field of therapeutic compounds, and more specifically to certain aryl-phenyl-sulfonamido-cycloalkyl compounds of the following formula (collectively referred to herein as “APSAC compounds”). The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, in treatment, for example, of inflammation and/or joint destruction and/or bone loss; of disorders mediated by excessive and/or inappropriate and/or prolonged activation of the immune system; of inflammatory and autoimmune disorders, for example, rheumatoid arthritis, psoriasis, psoriatic arthritis, chronic obstructive pulmonary disease (COPD), atherosclerosis, inflammatory bowel disease, ankylosing spondylitis, and the like; of disorders associated with bone loss, such as bone loss associated with excessive osteoclast activity in rheumatoid arthritis, osteoporosis, cancer-associated bone disease, Paget&#39;s disease and the like, etc.; and of cancer, such as a haematological malignancy, a solid tumour, etc. Formula (I).

RELATED APPLICATIONS

This application is a 35 U.S.C. §371 national phase application ofPCT/GB2009/002221, filed Sep. 18, 2009 (WO 2010/032009), entitled“Aryl-Phenyl-Sulfonamido-Cycloalkyl Compounds and Their Use”.PCT/GB2009/002221 is a non-provisional application of U.S. provisionalpatent application No. 61/098,271 filed Sep. 19, 2008 and United Kingdompatent application number 0817207.4 filed Sep. 19, 2008, the contents ofeach of which are incorporated herein by reference in their entirety.

TECHNICAL FIELD

The present invention pertains generally to the field of therapeuticcompounds, and more specifically to certainaryl-phenyl-sulfonamido-cycloalkyl compounds (collectively referred toherein as “APSAC compounds”). The present invention also pertains topharmaceutical compositions comprising such compounds, and the use ofsuch compounds and compositions, both in vitro and in vivo, intreatment, for example, of inflammation and/or joint destruction and/orbone loss; of disorders mediated by excessive and/or inappropriateand/or prolonged activation of the immune system; of inflammatory andautoimmune disorders, for example, rheumatoid arthritis, psoriasis,psoriatic arthritis, chronic obstructive pulmonary disease (COPD),atherosclerosis, inflammatory bowel disease, ankylosing spondylitis, andthe like; of disorders associated with bone loss, such as bone lossassociated with excessive osteoclast activity in rheumatoid arthritis,osteoporosis, cancer-associated bone disease, Paget's disease and thelike, etc.; and of cancer, such as a haematological malignancy, a solidtumour, etc.

BACKGROUND

A number of patents and publications are cited herein in order to morefully describe and disclose the invention and the state of the art towhich the invention pertains. Each of these references is incorporatedherein by reference in its entirety into the present disclosure, to thesame extent as if each individual reference was specifically andindividually indicated to be incorporated by reference.

Throughout this specification, including the claims which follow, unlessthe context requires otherwise, the word “comprise,” and variations suchas “comprises” and “comprising,” will be understood to imply theinclusion of a stated integer or step or group of integers or steps butnot the exclusion of any other integer or step or group of integers orsteps.

It must be noted that, as used in the specification and the appendedclaims, the singular forms “a,” “an,” and “the” include plural referentsunless the context clearly dictates otherwise. Thus, for example,reference to “a pharmaceutical carrier” includes mixtures of two or moresuch carriers, and the like.

Ranges are often expressed herein as from “about” one particular value,and/or to “about” another particular value. When such a range isexpressed, another embodiment includes from the one particular valueand/or to the other particular value. Similarly, when values areexpressed as approximations, by the use of the antecedent “about,” itwill be understood that the particular value forms another embodiment.

This disclosure includes information that may be useful in understandingthe present invention. It is not an admission that any of theinformation provided herein is prior art or relevant to the presentlyclaimed invention, or that any publication specifically or implicitlyreferenced is prior art.

Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory diseasecharacterised by painful swelling, stiffness, loss of movement and thedestruction of cartilage and bone. RA is characterised by aninflammation of the synovial lining of multiple joints and commonlyaffects the joints of the wrist and hands and may also affect theelbows, shoulders, hips, neck and knees; the ultimate hallmark of RA isjoint destruction. RA is a common disease, estimated to affect up to 1%of adults in the developed world, with women more than twice as likelyto be affected and over 30% of patients likely to become severelydisabled within 20 years (see, e.g., Feldmann et al., 2006). RA is oneof the most important causes of disability in the western world and isassociated with a significant reduction in quality of life as well asincreased mortality if left untreated. The disease can start at any age,with individuals aged between 40 and 70 most commonly affected.

The exact cause of RA remains unclear, but is highly complex and mayinvolve the combination of a number of factors which lead to thedevelopment of autoantibodies, formation of immune complexes, productionof pro-inflammatory cytokines, angiogenesis and eventual bone andcartilage loss (see, e.g., Klareskog et al, 2006; Ziff et al, 1990;Weissmann et al, 2006; Firestein et al, 2005). These factors include anabnormal immune response caused by reduced self tolerance or abiological trigger such as reaction to environmental factors, infectiousagents, or hormonal stimulus (see, e.g., Klareskog et al, 2006);antibodies to the Fc fragment of IgG, known as rheumatoid factor, arepresent in 60-80% of adults with RA (see, e.g., Weissmann et al, 2006)but it is not known whether this factor is responsible for initiatingthe inflammatory cascade or is generated at a later stage and propagatesthe process (see, e.g., Weissmann et al, 2006); there is also a notablegenetic predisposition to the disease, as shown by the presence ofHLA-DR4 antibody in 70% of patients (see, e.g., Klareskog et al, 2006).At the cellular level, development of RA usually commences with T-cellsinfiltrating the synovial membrane lining the affected joint; this thenleads to the activation of macrophages, monocytes and synovialfibroblasts (see, e.g., Firestein, 1996) by way of cell-cell contact andrelease of various cytokines, including TNFα and IL-1 (see, e.g.,Feldmann, 1996). Activation of these cells leads to the overproductionof a range of pro-inflammatory cytokines, of which the most importantare TNFα, IL-1 and IL-6 (see, e.g., Brennan et al, 1996; McInnes et al,2005). These pro-inflammatory cytokines are then instrumental inorchestrating several complex signal transduction cascades, includingthe NFκB, MAPK and Jak/STAT pathways (see, e.g., Firestein et al, 1999)which lead to the induction of genes coding for various products thatpropagate the inflammatory response and also promote tissue destruction.These products include tissue-degrading enzymes such as collagenases,matrix metalloproteases, cathepsins, and other pro-inflammatory factorssuch as selectins, integrins, leukotrienes, prostaglandins, chemokines,and other cytokines. Furthermore, TNFα and IL-1 also induce RANKLexpression.

RANKL is an essential factor for the generation of osteoclasts (see,e.g., Tanaka et al, 2003; Roodman, 2006), and upregulatedRANKL-production leads to increased osteoclast differentiation andultimately bone destruction (see, e.g., Tanaka et al, 2003; Roodman,2006). The inflammatory response leads to the accumulation of manyleukocytes and immune factor populations within the affected joint andalso to hyperplasia of the Type-A and Type-B synoviocytes (see, e.g.,Firestein et al, 2005), leading to thickening and vascularisation of thesynovium into a destructive and aggressive tissue known as a pannus. Thepannus contains both osteoclasts, which destroy bone, andmetalloproteases, which continue the destruction of cartilage.

Treatment of Rheumatoid Arthritis

Early therapies for RA focused on controlling the symptoms of thedisease, mainly by reduction of inflammation, rather than retardingdisease progression. These drugs included NSAIDs such as aspirin,diclofenac and naproxen and, until recently, the COX-2 selective drugsCelebrex® and Vioxx® were also widely used. Inflammation was furthercontrolled by glucocorticoids, and their combination with NSAIDsprovided reasonably effective short-term control of the inflammation.More recently, a more aggressive approach to treating RA has beenintroduced starting at disease onset, using so-called disease-modifyinganti-rheumatic drugs (DMARDs), which act to slow or even prevent diseaseprogression. These include a number of older drugs, including goldsalts; sulfasalazine; antimalarials such as hydroxychloroquine;D-penicillamine; immunosuppressants such as mycophenolic acid,azathioprine, cyclosporine A, tacrolimus and sirolimus; minocycline;leflunomide; and most importantly, methotrexate (see, e.g., Smolen etal, 2003).

Methotrexate is now the gold-standard therapy for clinical trialcomparisons, and is generally used in combination with newer therapies.It is effective in most patients but, in common with all of the aboveagents, has significant gastrointestinal side effects, which lead toroughly 50% of patients eventually having to cease treatment withmethotrexate (see, e.g., Mount et al, 2005). A further drawback of theseolder DMARDs is the length of time taken for the drug to start acting,ranging from weeks with methoxtrexate, to months with gold salts. Whilstfull remissions only occur in about a quarter of patients, for thoseshowing no effect it is not generally possible to stop therapy withoutsuffering the risk of a more violent disease rebound (see, e.g., Smolenet al, 2003). In recent years, the treatment of RA has beenrevolutionized by the advent of biological agents which target specificinflammatory pathways. The first and most important of these are theanti-tumour necrosis factor (anti-TNF) agents (see, e.g., Elliott et al,1994).

The Role of TNFα in RA

As discussed above, the TNF superfamily of receptors and ligands plays akey role in the causation of inflammation and associated local andsystemic bone loss. TNFα production within the joint may in fact playthe pivotal role in orchestrating the production of other factors whichleads to the persistence of inflammation and tissue damage (see, e.g.,Feldmann et al, 2001; Brennan et al, 1999; Brennan, 1992). Theimportance of TNFα in RA is highlighted by the finding that antibodiesblocking TNFα can prevent inflammation in animal models of RA, and thatanti-TNFα therapy is currently the most effective treatment for RA (see,e.g., Elliott et al, 1994; Feldmann et al, 1994; Joosten et al 1996,Klareskog et al, 2006). However, there is evidence that there are someTNFα-independent effects of IL-1 in RA, most notably bone destruction(see, e.g., van den Berg et al, 1999; van den Berg et al, 2002).

TNFα is a cytokine that effects many different functions, including thealteration of tissue remodelling, changes to the permeability of theepithelial cell barrier, activation of macrophages, up-regulation ofadhesion molecules, recruitment of other immune response effectors and,most importantly in RA, it instigates the signalling cascade which leadsto the activation of the transcription factors NFκB and AP-1 (see, e.g.,Liu, 2005; Baud et al, 1999). Binding of TNFα and IL-1 to theirrespective receptors leads to the recruitment of downstream signaltransducers called TRAFs. Further kinases are recruited by the TRAFs,and the resulting kinase complex activates the MAP-kinase pathway,ultimately leading to activation of AP-1, and the phosphorylation of IκBkinase. IκB is the inhibitor of NFκB, which acts by preventingtranslocation of NFκB to the nucleus. Phosphorylation of IκB by IκBkinase leads to degradation of IκB. Once IκB has been degraded, NFκBmigrates to the nucleus, where it promotes transcription ofanti-apoptotic genes, which promote survival of T and B-cells, therebyprolonging the immune response. This prolongation of the inflammatoryresponse is central to the chronic nature of RA. The importance of NFκBactivation is demonstrated by the fact that inhibition of NFκB activityby inhibitory peptides can prevent arthritis in animal models of RA(see, e.g., Jimi et al, 2004).

Anti-TNFα Therapy

Anti-TNFα therapy represents the market-leading therapies for RA, and isperformed either with neutralizing antibodies such as infliximab(Remicade® J&J and Schering Plough) and adalimumab (Humira®, Abbott) ordecoy receptors such as etanercept (Enbrel® Amgen and Wyeth), both whichrepresent validated and highly effective treatments for RA. Anti-TNFαbiologicals are already licensed for RA, Crohn's disease, and psoriasis.A number of other inflammatory and autoimmune disorders are also beinginvestigated as potential targets. Other approaches to blocking theaction of TNFα include the pegylated anti-TNFα fragment certolizumab(Cimzia®, UCB); inhibition of proximal signalling intermediates such asMAP kinase; interference with the synthesis of TNFα via inhibition ofTNFα converting enzyme (TACE); and inhibition of the metalloproteasesresponsible for cleaving TNFα from the cell surface (see, e.g., Smolenet al, 2003; Mount et al, 2005).

Other Inhibitors of NFκB Activation

As described above, the binding of IL-1 and RANKL to their receptorsalso initiates a signalling cascade, which eventually leads to theactivation of NFκB and subsequent inflammatory response. The efficacy ofinhibitors of these ligands has been validated by the use of the IL-1receptor antagonist anakinra (Kineret® Amgen) for the treatment of RA,and the completion of clinical trials for the monoclonal antibodyagainst RANKL AMG-162 (Denosumab® Amgen) for osteoporosis (it is also inclinical trials for RA and psoriasis).

Other Common Inflammatory Diseases Mediated by TNFα

There are several other common inflammatory diseases in which TNFα hasbeen shown to play a major role and in which TNFα inhibitors have foundtherapeutic use. These include inflammatory bowel disease (IBD) andpsoriasis.

IBD is an inflammatory disorder of the gut affecting about 0.25% of thepopulation in the western world, of which the two main forms are:ulcerative colitis (UC), in which the lining of the colon becomesinflamed and ulcerated; and Crohn's disease (CD), which can occuranywhere within the gastrointestinal tract, but most often the ileum,and commonly involves inflammation of the entire gut wall. Commonsymptoms of IBD are bloody diarrhea and abdominal pain.

Psoriasis is an inflammatory response of the skin affecting 1-3% of thepopulation in the western world. The disease is characterised by raised,red, scaly plaques on the skin, which may be itchy and also causesignificant psychological distress by their unsightly nature. A furthercomplication of psoriasis is the development of psoriatic arthritis, aninflammatory arthritis of the joints, in up to 40% of patients, whichdevelops on average 10 years after the first symptoms of skin diseaseare seen (see, e.g., Gottlieb, 2005).

As with RA, the etiology of IBD and psoriasis are unknown and mayinvolve a complex combination of infectious agents, environmental, andgenetic factors, generating an inappropriate and prolonged inflammatoryresponse.

Treatment of IBD and psoriasis has followed a similar pattern to that ofRA, with the past use of immunoregulatory agents such as NSAIDs,methotrexate, cyclosporine, steroids, and antimetabolites such as6-mercaptopurine for IBD (see, e.g., Korzenik et al, 2006) andmethotrexate and cyclosporine for psoriasis (see, e.g., Gottlieb, 2005).The treatment of both has been revolutionized by the advent ofbiological agents, in particular those which block TNFα signalling.Etanercept is licensed for the treatment of psoriasis and psoriaticarthritis; both infliximab and adalimumab are licensed for psoriaticarthritis, IBD, and psoriasis.

Cancer

There is growing evidence that activation of NFκB can play a major rolein the promotion and progression of both haematological malignancies,such as myeloma and lymphomas, and solid tumours, such as breast,prostate and lung cancer (see, e.g., Baud and Karin, 2009). There isalso rising awareness of the role and importance of inflammation incancer and in the development of resistance to radiotherapy and tochemotherapeutic agents, and it has been suggested that inflammation isin fact one of the basic hallmarks of cancer (see, e.g., Mantovani,2009). Improving the efficacy of anti-cancer treatments by prevention ofNFκB activation is therefore a promising strategy to augment existingtherapeutic regimes and is currently under investigation, most notablyfor the treatment of multiple myeloma.

Defects in the normal apoptotic pathways are also implicated in thedevelopment and progression of tumour cell growth. Apoptosis (programmedcell death) plays a key role in the removal of abnormal cells; defectsin the signalling cascades, which would normally lead to its induction,play a key role in oncogenesis. Radiotherapy and many chemotherapeuticagents act by causing cellular damage, which would normally induceapoptosis; defects in the pathway will therefore also reduce theeffectiveness of such agents. The most important effector molecules inthe signalling pathway leading to apoptosis are known as the caspases,which may be triggered by a number of stimuli, including TNFα binding toits receptor. Mutations in the genes which encode for the caspases havebeen found in a number of tumour types, including gastric, breast, renalcell and cervical cancers as well as commonly in T-cell lymphoblasticlymphoma and basal cell ameloblastomas (see, e.g., Philchenkov et al.,2004). Compounds which activate caspases, and thus sensitise cells toapoptosis, would be highly effective as cancer therapies either assingle agents or in enhancing the effectiveness of existing cancerchemotherapy and radiotherapy.

Common Bone Diseases

Osteoporosis is a common disease characterised by reduced bone density,deterioration of bone tissue, and an increased risk of fracture. Manyfactors contribute to the pathogenesis of osteoporosis including poordiet, lack of exercise, smoking, and excessive alcohol intake.Osteoporosis may also arise in association with inflammatory diseasessuch as rheumatoid arthritis, endocrine diseases such as thyrotoxicosis,and with certain drug treatments such as treatment with glucocorticoids.However one of the most important factors in the pathogenesis ofosteoporosis is heredity.

Paget's disease of bone is a common condition of unknown cause,characterised by increased bone turnover and disorganised boneremodelling, with areas of increased osteoclastic and osteoblastactivity. Although Pagetic bone is often denser than normal, theabnormal architecture causes the bone to be mechanically weak, resultingin bone deformity and increased susceptibility to pathological fracture.

Many types of cancer affect bone. Cancer-associated bone disease can bemanifest by the occurrence of hypercalcemia or the development ofosteolytic and/or osteosclerotic metastases. Increased osteoclastic boneresorption plays a key role in the pathogenesis of both conditions.Whilst almost any cancer can be complicated by bone metastases, the mostcommon sources are multiple myeloma, breast carcinoma, and prostatecarcinoma. The most common tumours associated with hypercalcemia aremultiple myeloma, breast carcinoma, and lung carcinoma.

RANKL signalling has been shown to play a major role in osteoclastover-activity and a consequent increase in bone loss (see, e.g., Tanakaet al, 2003; Roodman, 2006). The use of drugs which affect this pathwayhas been validated by the completion of clinical trials of themonoclonal antibody against RANKL AMG-162 (Denosumab® Amgen) for thetreatment of osteoporosis/multiple myeloma.

As described previously, bone loss also plays a major role in thepathophysiology of rheumatoid arthritis and drugs which preventactivation of the signalling pathways described (e.g. TNFα blockers) arealso able to prevent this bone loss.

Agents That Prevent Inflammation and/or Bone Loss

The inventors have identified a new class of compounds which, forexample, prevent inflammation and/or bone loss, and thus may be used inthe treatment of diseases with an inflammatory or autoimmune component,including, for example, rheumatoid arthritis, inflammatory boweldisease, psoriasis, and psoriatic arthritis; diseases which involve boneloss, including, for example, bone loss associated with rheumatoidarthritis, osteoporosis, Paget's disease of bone, and multiple myeloma;as well as cancer associated with activation of NFκB, with aberrant NFκBsignaling, or with inflammation, including haematological malignanciessuch as multiple myeloma, leukaemia, T-cell lymphoblastic lymphoma, andother lymphoma (e.g., non-Hodgkin Lymphoma), and solid tumours such ascancer of the bladder, breast cancer (female and/or male), colon cancer,kidney cancer, lung cancer, pancreatic cancer, prostate cancer, braincancer, skin cancer, thyroid cancer, and melanoma; and cancer associatedwith the inactivation or impairment of caspase-mediated cell death, suchas gastric cancer, breast cancer, renal cancer, cervical cancer, andbasal cell ameloblastomas.

Without wishing to be bound by any particular theory, the inventorsbelieve that this action may be via a mechanism that involves blockingTNFα and/or IL-1 and/or RANKL-signalling.

Biphenyl Sulfonamides

Greig et al., 2004 and Greig et al., 2006 describe a class of biphenylalkyl sulfonamides as anti-resorptive agents for the treatment of bonediseases, including, for example, 2′,4′-difluoro-biphenyl-4-sulfonicacid (5-hydroxy-pentyl)-amide (ABD248) and2′,4′-difluoro-biphenyl-4-sulfonic acid (4-hydroxy-butyl)-amide (ABD256)(shown below).

Greig et al., 2008 (not yet published), describes a class of biphenylalkyl sulfonamides, as anti-resorptive agents for the treatment of bonediseases including, for example, 2′,4′-difluoro-biphenyl-4-sulfonic acid(3-hydroxymethyl-phenyl)-amide (ABD456),2′,4′-difluoro-biphenyl-4-sulfonic acid (4-hydroxymethyl-phenyl)-amide(ABD466), and 2′,4′-difluoro-biphenyl-4-sulfonic acid[3-(2-hydroxy-ethyl)-phenyl]-amide (ABD628), shown below.

It appears that compounds of the following formulae may be known:

No. Structure Registry No. 1

297742-90-6 2

496015-30-6 3

496015-31-7 4

855253-65-5 5

857624-18-1 6

301354-93-8 7

667901-42-0 8

1022412-74-3 9

326499-72-3 10

326500-04-3 11

326500-05-4 12

326499-76-7 13

326499-74-5 14

326499-73-4 15

220441-06-5 16

220441-14-5 17

220441-05-4 18

866043-75-6 866043-74-5 19

866043-71-2 866043-66-5 866043-65-4 20

848632-03-1 848494-84-8

The present inventors have identified a new a class of arylsulfonamides, as defined herein, that have surprising and unexpectedproperties.

The present inventors have identified a new a class of arylsulfonamides, as defined herein, that have, inter alia, one or moresurprising and unexpected properties.

Without wishing to be bound to any particular theory, the inventorsbelieve that the new compounds have been protected against the majorroute of metabolism acting upon the previous biphenyl aryl sulfonamides(specifically, oxidation of the terminal alcohol to give a carboxylicacid) by the replacement of the aryl ring with a carbocyclic group; thismay also be further combined with replacement of the alcohol by anamine. In addition to the resulting substantial improvement in metabolicstability, these replacement groups have also been selected to provide afurther substantial enhancement in the aqueous solubility of thecompounds. If a drug is to show oral activity, it must first besolvated, to permit absorption from the gastrointestinal tract. Second,the drug must be sufficiently resistant to first-pass metabolism bymetabolic enzymes contained within the liver so as to be able to enterthe circulation and permit sufficient quantities to reach the biologicaltarget. Third, the drug must be sufficiently potent against thebiological target to give the desired therapeutic effect.

The optimization of pharmacokinetic properties (action of the body onthe drug) of a drug is a developmental barrier of equal challenge ascompared to the optimization of pharmacodynamic properties (action ofthe drug on the body). By improving both solubility and stability, withlittle or no loss of potency against the biological target, the newcompounds disclosed herein show substantial improvements in theirproperties as oral therapeutic agents, as compared to previous compoundsidentified above. The new compounds combine the characteristics requiredof orally active agents for the treatment of inflammatory diseasesand/or for the treatment of bone loss.

SUMMARY OF THE INVENTION

One aspect of the invention pertains to certainaryl-phenyl-sulfonamido-cycloalkyl compounds (for convenience,collectively referred to herein as “APSAC compounds”), as describedherein.

Another aspect of the invention pertains to a composition (e.g., apharmaceutical composition) comprising an APSAC compound, as describedherein, and a pharmaceutically acceptable carrier or diluent.

Another aspect of the invention pertains to method of preparing acomposition (e.g., a pharmaceutical composition) comprising the step ofadmixing an APSAC compound, as described herein, and a pharmaceuticallyacceptable carrier or diluent.

Another aspect of the invention pertains to a method of inhibiting aninflammatory response, in vitro or in vivo, comprising contacting animmune system component with an effective amount of an APSAC compound,as described herein.

Another aspect of the invention pertains to a method of inhibitingcellular and/or molecular pathways leading to joint destruction, invitro or in vivo, comprising contacting cells associated with an immuneresponse with a therapeutically-effective amount of an APSAC compound,as described herein.

Another aspect of the invention pertains to a method of inhibitingosteoclast survival, formation, and/or activity, in vitro or in vivo,comprising contacting an osteoclast with an effective amount of an APSACcompound, as described herein.

Another aspect of the invention pertains to a method of inhibiting boneresorption, in vitro or in vivo, comprising contacting cells in the bonemicroenvironment with a therapeutically-effective amount of an APSACcompound, as described herein.

Another aspect of the present invention pertains to a method oftreatment comprising administering to a subject in need of treatment atherapeutically-effective amount of an APSAC compound, as describedherein, preferably in the form of a pharmaceutical composition.

Another aspect of the present invention pertains to an APSAC compound asdescribed herein for use in a method of treatment of the human or animalbody by therapy.

Another aspect of the present invention pertains to use of an APSACcompound, as described herein, in the manufacture of a medicament foruse in treatment.

In one embodiment, the treatment is treatment of inflammation and/orjoint destruction and/or bone loss.

In one embodiment, the treatment is treatment of disorders mediated byexcessive and/or inappropriate and/or prolonged activation of the immunesystem.

In one embodiment, the treatment is treatment of inflammatory andautoimmune disorders, for example, rheumatoid arthritis, psoriasis,psoriatic arthritis, chronic obstructive pulmonary disease (COPD),atherosclerosis, inflammatory bowel disease, ankylosing spondylitis, andthe like.

In one embodiment, the treatment is treatment of inflammatory andautoimmune disorders, for example, rheumatoid arthritis, psoriasis,psoriatic arthritis, inflammatory bowel disease, ankylosing spondylitis,and the like.

In one embodiment, the treatment is treatment of disorders associatedwith bone loss, such as bone loss associated with excessive osteoclastactivation in rheumatoid arthritis, osteoporosis, cancer-associated bonedisease, Paget's disease and the like.

In one embodiment, the treatment is treatment of a haematologicalmalignancy, e.g., multiple myeloma, leukaemia, or lymphoma (e.g.,non-Hodgkin Lymphoma), e.g., a haematological malignancy, multiplemyeloma, leukaemia, or lymphoma (e.g., non-Hodgkin Lymphoma) associatedwith activation of NFκB, with aberrant NFκB signalling, or withinflammation, e.g., alone, or in combination with, and to augment theefficacy of, radiotherapy or chemotherapy.

In one embodiment, the treatment is treatment of a solid tumour cancer,e.g., cancer of the bladder, breast cancer (female and/or male), coloncancer, kidney cancer, lung cancer, pancreatic cancer, prostate cancer,brain cancer, skin cancer, thyroid cancer, or melanoma, e.g., a solidtumour cancer, cancer of the bladder, breast cancer (female and/ormale), colon cancer, kidney cancer, lung cancer, pancreatic cancer,prostate cancer, brain cancer, skin cancer, thyroid cancer, and melanomaassociated with activation of NFκB, with aberrant NFκB signalling, orwith inflammation, e.g., alone, or in combination with, and to augmentthe efficacy of, radiotherapy or chemotherapy.

In one embodiment, the treatment is treatment of a haematologicalmalignancy, e.g., T-cell lymphoblastic lymphoma, mantle cell lymphoma,or acute lymphoblastic leukemia, e.g., a haematological malignancy,T-cell lymphoblastic lymphoma, mantle cell lymphoma, or acutelymphoblastic leukemia associated with inactivation or impairment ofcaspase induction or with aberrant caspase signalling, e.g., alone or incombination with, and to augment the efficacy of, radiotherapy orchemotherapy.

In one embodiment, the treatment is treatment of a solid tumour cancer,e.g., renal cell carcinoma, breast cancer (female and/or male), gastriccancer, prostate cancer, colon cancer, or basal cell ameloblastoma,e.g., a solid tumour cancer, e.g., renal cell carcinoma, breast cancer(female and/or male), gastric cancer, prostate cancer, colon cancer, orbasal cell ameloblastoma associated with inactivation or impairment ofcaspase induction or with aberrant caspase signalling, e.g., alone, orin combination with, and to augment the efficacy of, radiotherapy orchemotherapy.

In one embodiment, the treatment is part of treatment by combinationtherapy, e.g., in combination with, and to augment the efficacy of,radiotherapy or chemotherapy.

Another aspect of the present invention pertains to a kit comprising (a)an APSAC compound, as described herein, preferably provided as apharmaceutical composition and in a suitable container and/or withsuitable packaging; and (b) instructions for use, for example, writteninstructions on how to administer the compound.

Another aspect of the present invention pertains to an APSAC compoundobtainable by a method of synthesis as described herein, or a methodcomprising a method of synthesis as described herein.

Another aspect of the present invention pertains to an APSAC compoundobtained by a method of synthesis as described herein, or a methodcomprising a method of synthesis as described herein.

Another aspect of the present invention pertains to novel intermediates,as described herein, which are suitable for use in the methods ofsynthesis described herein.

Another aspect of the present invention pertains to the use of suchnovel intermediates, as described herein, in the methods of synthesisdescribed herein.

As will be appreciated by one of skill in the art, features andpreferred embodiments of one aspect of the invention will also pertainto other aspect of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing mean plasma concentration (ng/mL) of the APSACcompound ABD773 (▪) after oral administration (1 mg/kg) to a rat model.

FIG. 2 is a graph showing mean plasma concentration (ng/mL) of the APSACcompound ABD773 (▪) after intravenous administration (1 mg/kg) to a ratmodel.

FIG. 3 is a graph showing mean plasma concentration (ng/mL) of the APSACcompound ABD781 (▪) after oral administration (1 mg/kg) to a rat model.

FIG. 4 is a graph showing mean plasma concentration (ng/mL) of the APSACcompound ABD781 (▪) after intravenous administration (1 mg/kg) to a ratmodel.

FIG. 5 is a graph showing mean plasma concentration (μg/mL) of thereference compound ABD455 (▪) after oral administration (2.5 mg/kg) to arat model.

FIG. 6 is a graph showing mean plasma concentration (μg/mL) of thereference compound ABD455 (▪) after intravenous administration (2.5mg/kg) to a rat model.

FIG. 7 is a series of images of human monocytes monitored usingfluorescent light microscopy and showing the effects of ABD599 andABD781 on caspase 3 activation in the presence of TNFα: (a) TNFα alone;(b) TNFα with 10 μM ABD599, and (c) TNFα with 10 μM ABD781.

DETAILED DESCRIPTION OF THE INVENTION

Compounds

The compounds of the present invention are structurally related to1-(aryl)-phenyl-4-sulfonic acid cyclohexyl amide:

One aspect of the present invention pertains to compounds of thefollowing formula, and pharmaceutically acceptable salts, hydrates, andsolvates thereof (collectively referred to herein as“aryl-phenyl-sulfonamido-cycloalkyl” or “APSAC compounds”):

wherein:

-   -   -A is independently:

-   -   —Ar is independently phenyl, pyridinyl, or pyrimidinyl; and    -   p is independently an integer from 0 to 3;        and wherein:    -   q is independently an integer from 0 to 3;        and wherein:    -   —R^(SN) is independently —H or saturated aliphatic C₁₋₄alkyl;        and wherein:    -   -DQ is independently -D¹-Q¹ or -D²=O;    -   -D¹- is independently cyclopentane-di-yl, cyclohexane-di-yl,        cycloheptane-di-yl, bicyclo[3.1.1]heptane-di-yl, or        bicyclo[3.2.1]octane-di-yl, and is optionally substituted with        one or more groups —R^(D);    -   -D²= is independently cyclopentane-yl-ylidene,        cyclohexane-yl-ylidene, cycloheptane-yl-ylidene,        bicyclo[3.1.1]heptane-yl-ylidene, or        bicyclo[3.2.1]octane-yl-ylidene, and is optionally substituted        with one or more groups —R^(D);    -   each —R^(D) is independently selected from —F, —Cl, —Br, —I,        —R^(DD), —CF₃, —OH, —OR^(DD), —NH₂, —NHR^(DD), and —NR^(DD) ₂;        and    -   each —R^(DD) is independently saturated aliphatic C₁₋₄alkyl;        and wherein -Q¹ is independently selected from:

wherein:

-   -   each —R^(1N) is independently —H, —R^(CN), or —R^(CF);    -   each —R^(2N) is independently —H, —R^(CN), or —R^(CF);    -   each —R^(CN) is independently saturated aliphatic C₁₋₄alkyl;    -   each —R^(CF) is independently saturated aliphatic        C₁₋₄fluoroalkyl;    -   or:    -   —NR^(1N)R^(2N) is independently azetidino, pyrrolidino,        imidazolidino, pyrazolidino, piperidino, piperazino, morpholino,        thiomorpholino, azepino, or diazepino, each optionally        substituted with one or more groups independently selected from        saturated aliphatic C₁₋₄alkyl;    -   —R^(1A) is independently —H, —R^(C), or —R^(F); and    -   —R^(2A) is independently —H, —R^(C), or —R^(F);    -   or —R^(1A) and —R^(2A) together form a saturated aliphatic        C_(2A)alkylene group;    -   —R^(1B) is independently —H, —R^(C), or —R^(F); and    -   —R^(2B) is independently —H, —R^(C), or —R^(F);    -   or —R^(1B) and —R^(2B) together form a saturated aliphatic        C₂₋₄alkylene group;    -   or —R^(1B) and —R^(2B) together form ═O;    -   —R^(3A) is independently —H, —R^(C), or —R^(F); and    -   —R^(4A) is independently —H, —R^(C), or —R^(F);    -   or —R^(3A) and —R^(4A) together form a saturated aliphatic        C₂₋₄alkylene group; —R^(5A) is independently —H, —R^(C), —R^(F),        or —R^(J); and    -   —R^(6A) is independently —H, —R^(C), or —R^(F);    -   or —R^(5A) and —R^(6A) together form a saturated aliphatic        C₂₋₄alkylene group;    -   —R^(3B) is independently —H, —R^(C), or —R^(F); and    -   —R^(4B) is independently —H, —R^(C), or —R^(F);    -   or —R^(3B) and —R^(4B) together form a saturated aliphatic        C₂₋₄alkylene group;    -   —R^(5B) is independently —H, —R^(C), —R^(F), —OH, or —OR^(O);        and    -   —R^(6B) is independently —H, —R^(C), or —R^(F);    -   or —R^(5B) and —R^(6B) together form a saturated aliphatic        C₂₋₄alkylene group;    -   each —R^(C) is independently saturated aliphatic C₁₋₄alkyl;    -   each —R^(F) is independently saturated aliphatic        C₁₋₄fluoroalkyl;    -   —R^(O) is independently saturated aliphatic C₁₋₄alkyl;    -   —R^(J) is independently —NH₂, —NHR^(JN1), —NR^(JN1) ₂, or        —NR^(JN2)R^(JN3);    -   each —R^(JN1) is independently saturated aliphatic C₁₋₄alkyl;        and    -   —NR^(JN2)R^(JN3) is independently azetidino, pyrrolidino,        imidazolidino, pyrazolidino, piperidino, piperazino, morpholino,        thiomorpholino, azepino, or diazepino, each optionally        substituted with one or more groups independently selected from        saturated aliphatic C₁₋₄alkyl;        and wherein each —R^(X) is independently:    -   —F, —Cl, —Br, —I,    -   —R^(XX),    -   —OH, —OR^(XX),    -   —SH, —SR^(XX),    -   —CF₃, —OCF₃, —SCF₃,    -   —NH₂, —NHR^(XX), —NR^(XX) ₂, —NR^(YY)R^(ZZ),    -   —C(═O)R^(XX), —OC(═O)R^(XX),    -   —C(═O)OH, —C(═O)OR^(XX),    -   —C(═O)NH₂, —C(═O)NHR^(XX), —C(═O)NR^(XX) ₂, —C(═O)NR^(YY)R^(ZZ),    -   —OC(═O)NH₂, —OC(═O)NHR^(XX), —OC(═O)NR^(XX) ₂,        —OC(═O)NR^(YY)R^(ZZ),    -   —NHC(═O)R^(XX), —NR^(XX)C(═O)R^(XX),    -   —NHC(═O)OR^(XX), —NR^(XX)C(═O)OR^(XX),    -   —NHC(═O)NH₂, —NHC(═O)NHR^(XX), —NHC(═O)NR^(XX) ₂,        —NHC(═O)NR^(YY)R^(ZZ),    -   —NR^(XX)C(═O)NH₂, —NR^(XX)C(═O)NHR^(XX), —NR^(XX)C(═O)NR^(XX) ₂,        —NR^(XX)C(═O)NR^(YY)R^(ZZ),    -   —CN,    -   —NO₂,    -   —S(═O)₂NH₂, —S(═O)₂NHR^(XX), —S(═O)₂NR^(XX) ₂,        —S(═O)₂NR^(YY)R^(ZZ),    -   —S(═O)R^(XX), —S(═O)₂R^(XX), —OS(═O)₂R^(XX), —S(═O)₂OH, or        —S(═O)₂OR^(XX);    -   wherein:    -   each —R^(XX) is independently saturated aliphatic C₁₋₆alkyl,        phenyl, or benzyl, wherein said phenyl and benzyl are optionally        substituted with one or more groups selected from: —F, —Cl, —Br,        —I, —CF₃, —OCF₃, —R^(XXX), —OH, —OR^(XXX), or —SR^(XXX), wherein        each —R^(XXX) is independently saturated aliphatic C₁₋₄alkyl;        and    -   each —NR^(YY)R^(ZZ) is independently azetidino, pyrrolidino,        imidazolidino, pyrazolidino, piperidino, piperazino, morpholino,        thiomorpholino, azepino, or diazepino, each optionally        substituted with one or more groups independently selected from        saturated aliphatic C₁₋₄alkyl.        The Group -A

In one embodiment, -A is independently:

In one embodiment, —Ar is independently phenyl, pyridinyl, orpyrimidinyl.

In one embodiment, —Ar is independently phenyl.

In one embodiment, —Ar is independently pyridinyl.

In one embodiment, —Ar is independently pyridin-2-yl.

In one embodiment, —Ar is independently pyridin-3-yl.

In one embodiment, —Ar is independently pyridin-4-yl.

In one embodiment, —Ar is independently pyrimidinyl.

In one embodiment, —Ar is independently pyrimidin-2-yl.

In one embodiment, —Ar is independently pyrimidin-4-yl.

In one embodiment, —Ar is independently pyrimidin-5-yl.

Substituents on —Ar

In one embodiment, p is independently an integer from 0 to 3.

In one embodiment, p is independently an integer from 1 to 3.

In one embodiment, p is independently 0.

In one embodiment, p is independently 1.

In one embodiment, p is independently 2.

In one embodiment, p is independently 3.

The Group -A: Phenyl and Pyridinyl

In one embodiment, -A is independently:

wherein:

-   -   ═W— is —CH═ or —CR^(W)═ and —Y═ is —CH═ or —CR^(Y)═; or    -   ═W— is —CH═ or —CR^(W)═ and —Y═ is —N═; or    -   ═W— is —N═ and —Y═ is —CH═ or —CR^(Y)═;    -   —R^(W) is independently saturated aliphatic C₁₋₄alkyl;    -   —R^(Y) is independently saturated aliphatic C₁₋₄alkyl;    -   —R^(X2) is independently —H or —R^(X2S);    -   —R^(X3) is independently —H or —R^(X3S);    -   —R^(X4) is independently —H or —R^(X4S);    -   —R^(X2S) is independently —R^(X);    -   —R^(X3S) is independently —R^(X); and    -   —R^(X4S) is independently —R^(X).

In one embodiment, -A is independently:

In one embodiment, -A is independently:

In one embodiment, -A is independently:

The Group -A: Phenyl and Pyridinyl: the Groups ═W— and —Y═

In one embodiment, ═W— is —CH═ or —CR^(W)═ and —Y═ is —CH═ or —CR^(Y)═.

In one embodiment, ═W— is —CH═ and —Y═ is —CH═, as in, for example:

In one embodiment, ═W— is —CH═ or —CR^(W)═ and —Y═ is —N═.

In one embodiment, ═W— is —CH═ and —Y═ is —N═, as in, for example:

In one embodiment, ═W— is —N═ and —Y═ is —CH═ or —CR^(Y)═.

In one embodiment, ═W— is —N═ and —Y═ is —CH═, as in, for example:

In one embodiment, —R^(W), if present, is independently saturatedaliphatic C₁₋₄alkyl.

In one embodiment, —R^(W), if present, is independently -Me.

In one embodiment, —R^(Y), if present, is independently saturatedaliphatic C₁₋₄alkyl.

In one embodiment, —R^(Y), if present, is independently -Me.

The Group -A: Phenyl: R^(X2) and R^(X4)

In one embodiment, -A is independently:

wherein:

-   -   —R^(X2) is independently —H or —R^(X2S);    -   —R^(X4) is independently —H or —R^(X4S);    -   —R^(X2S) is independently —R^(X); and    -   —R^(X4S) is independently —R^(X).        The Group —R^(X2)

In one embodiment, —R^(X2), if present, is independently —H or —R^(X2S).

In one embodiment, —R^(X2), if present, is independently —R^(X2S).

In one embodiment, —R^(X2), if present, is independently —H.

The Group —R^(X3)

In one embodiment, —R^(X3), if present, is independently —H or —R^(X3S).

In one embodiment, —R^(X3), if present, is independently —R^(X3S).

In one embodiment, —R^(X3), if present, is independently —H.

The Group —R^(X4)

In one embodiment, —R^(X4), if present, is independently —H or —R^(X4S).

In one embodiment, —R^(X4), if present, is independently —R_(X4S).

In one embodiment, —R^(X4), if present, is independently —H.

Leading Phenylene Group

For the avoidance of doubt, the leading phenylene group is the phenylenegroup that links the group -A, on the left, with the group—S(═O)₂N(R^(S)N)(DQ), on the right.

And so, in one embodiment, the leading phenylene group is:

In one embodiment, q is independently an integer from 0 to 3.

In one embodiment, q is independently an integer from 1 to 3.

In one embodiment, q is independently 0.

In one embodiment, q is independently 1.

In one embodiment, q is independently 2.

In one embodiment, the leading phenylene group is:

wherein:

-   -   —R^(XC1) is independently —H or —R^(X); and    -   —R^(XC2) is independently —H or —R^(X).

In one embodiment:

-   -   —R^(XC1) is independently —H or —R^(X); and    -   —R^(XC2) is independently —H;        or:    -   —R^(XC1) is independently —H; and    -   —R^(XC2) is independently —H or —R^(X);        or:    -   —R^(XC1) is independently —H; and    -   —R^(XC2) is independently —H.        In one embodiment:    -   —R^(XC1) is independently —H; and    -   —R^(XC2) is independently —H or —R^(X).        In one embodiment:    -   —R^(XC1) is independently —H or —R^(X); and    -   —R^(XC2) is independently —H.        In one embodiment:    -   —R^(XC1) is independently —H; and —R^(XC2) is independently —H.        The Group —R^(X)

In one embodiment, each —R^(X), if present, is independently:

-   -   —F, —Cl, —Br, —I,    -   —R^(XX),    -   —OH, —OR^(XX),    -   —SH, —SR^(XX),    -   —CF₃, —OCF₃, —SCF₃,    -   —NH₂, —NHR^(XX), —NR^(XX) ₂, —NR^(YY)R^(ZZ),    -   —C(═O)R^(XX), —OC(═O)R^(XX),    -   —C(═O)OH, —C(═O)OR^(XX),    -   —C(═O)NH₂, —C(═O)NHR^(XX), —C(═O)NR^(XX) ₂, —C(═O)NR^(YY)R^(ZZ),    -   —OC(═O)NH₂, —OC(═O)NHR^(XX), —OC(═O)NR^(XX) ₂,        —OC(═O)NR^(YY)R^(ZZ),    -   —NHC(═O)R^(XX), —NR^(XX)C(═O)R^(XX),    -   —NHC(═O)OR^(XX), —NR^(XX)C(═O)OR^(XX),    -   —NHC(═O)NH₂, —NHC(═O)NHR^(XX), —NHC(═O)NR^(XX) ₂,        —NHC(═O)NR^(YY)R^(ZZ),    -   —NR^(XX)C(═O)NH₂, —NR^(XX)C(═O)NHR^(XX), —NR^(XX)C(═O)NR^(XX) ₂,        —NR^(XX)C(═O)NR^(YY)R^(ZZ),    -   —CN,    -   —NO₂,    -   —S(═O)₂NH₂, —S(═O)₂NHR^(XX), —S(═O)₂NR^(XX) ₂,        —S(═O)₂NR^(YY)R^(ZZ),    -   —S(═O)R^(XX), —S(═O)₂R^(XX), —OS(═O)₂R^(XX), —S(═O)₂OH, or        —S(═O)₂OR^(XX);    -   wherein:    -   each —R^(XX) is independently saturated aliphatic C₁₋₆alkyl,        phenyl, or benzyl, wherein said phenyl and benzyl are optionally        substituted with one or more groups selected from: —F, —Cl, —Br,        —I, —CF₃, —OCF₃, —R^(XXX), —OH, —OR^(XXX), or —SR^(XXX), wherein        each —R^(XXX) is independently saturated aliphatic C₁₋₄alkyl;        and    -   each —NR^(YY)R^(ZZ) is independently azetidino, pyrrolidino,        imidazolidino, pyrazolidino, piperidino, piperazino, morpholino,        thiomorpholino, azepino, or diazepino, each optionally        substituted with one or more groups independently selected from        saturated aliphatic C₁₋₄alkyl.

In one embodiment, each —R^(X), if present, is independently:

-   -   —F, —Cl, —Br, —I,    -   —R^(XX),    -   —OH, —OR^(XX),    -   —SH, —SR^(XX),    -   —CF₃, —OCF₃, —SCF₃,    -   —NH₂, —NHR^(XX), —NR^(XX) ₂, —NR^(YY)R^(ZZ),    -   —C(═O)R^(XX), —OC(═O)R^(XX),    -   —C(═O)OH, —C(═O)OR^(XX),    -   —C(═O)NH₂, —C(═O)NHR^(XX), —C(═O)NR^(XX) ₂, —C(═O)NR^(YY)R^(ZZ),    -   —CN,    -   —NO₂,    -   —S(═O)₂NH₂, —S(═O)₂NHR^(XX), —S(═O)₂NR^(XX) ₂, or        —S(═O)₂NR^(YY)R^(ZZ).

In one embodiment, each —R^(X), if present, is independently —F, —Cl,—Br, —I, —R^(XX), —OH, —OR^(XX), —SR^(XX), —CF₃, —OCF₃, —SCF₃,—C(═O)R^(XX), —CN, or —NO₂.

In one embodiment, each —R^(X), if present, is independently —F, —Cl,—Br, —I, —R^(XX), —OH, —OR^(XX), —SR^(XX), —CF₃, —OCF₃, —SCF₃, —CN, or—NO₂.

In one embodiment, each —R^(X), if present, is independently —F, —Cl,—Br, —I, —R^(XX), —OH, —OR^(XX), —SR^(XX), —CF₃, —OCF₃, —CN, or —NO₂.

In one embodiment, each —R^(X), if present, is independently —F, —Cl,—Br, —I, —R^(XX), —OR^(XX), —SR^(XX), —CF₃, or —OCF₃.

In one embodiment, each —R^(XX), if present, is independently saturatedaliphatic C₁₋₆alkyl, phenyl, or benzyl.

In one embodiment, each —R^(XX), if present, is independently saturatedaliphatic C₁₋₆alkyl.

In one embodiment, each —R^(XX), if present, is independently saturatedaliphatic C₁₋₄alkyl.

In one embodiment, —NR^(YY)R^(ZZ), if present, is independentlypyrrolidino, imidazolidino, pyrazolidino, piperidino, piperazino, ormorpholino, each optionally substituted with one or more groupsindependently selected from saturated aliphatic C₁₋₄alkyl.

In one embodiment, —NR^(YY)R^(ZZ), if present, is independentlypyrrolidino, piperidino, piperazino, or morpholino, each optionallysubstituted with one or more groups independently selected fromsaturated aliphatic C₁₋₄alkyl.

Substituents on the Leading Phenylene Group

In one embodiment, the leading phenylene group is:

wherein:

-   -   —R^(XC1) is independently —H or —R^(XCC); and    -   —R^(XC2) is independently —H or —R^(XCC);        wherein each —R^(XCC) is independently:    -   —F, —Cl, —R^(XCCC), —OR^(XCCC), —CF₃, —OCF₃;        wherein each —R^(XCCC) is independently saturated aliphatic        C₁₋₄alkyl.

In one embodiment:

-   -   —R^(XC1) is independently —H or —R^(XCC); and    -   —R^(XC2) is independently —H;        or:    -   —R^(XC1) is independently —H; and    -   —R^(XC2) is independently —H or —R^(XCC);        or:    -   —R^(XC1) is independently —H; and    -   —R^(XC2) is independently —H.        In one embodiment:    -   —R^(XC1) is independently —H; and    -   —R^(XC2) is independently —H or —R^(XCC).        In one embodiment:    -   —R^(XC1) is independently —H or —R^(XCC); and    -   —R^(XC2) is independently —H.        In one embodiment:    -   —R^(XC1) is independently —H; and    -   —R^(XC2) is independently —H.

In one embodiment, each —R^(XCC), if present, is independently —F, —Cl,or —R^(XCCC).

In one embodiment, each —R^(XCC), if present, is independently—R^(XCCC).

In one embodiment, each —R^(XCCC), if present, is independently -Me,-Et, -nPr, or -iPr.

In one embodiment, each —R^(XCCC), if present, is independently -Me or-Et.

The Group —R^(X2S)

In one embodiment, —R^(X2S), if present, is independently —R^(X).

In one embodiment, —R^(X2S), if present, is independently —F, —Cl, —Br,—I, —R^(XA), —OR^(XA), —SR^(XA), —CF₃, or —OCF₃, wherein each —R^(XA) isindependently saturated aliphatic C₁₋₄alkyl.

In one embodiment, —R^(X2S), if present, is independently —F, —Cl, —Br,—I, —R^(XA), —OR^(XA), —CF₃, or —OCF₃.

In one embodiment, —R^(X2S), if present, is independently —F, —Cl, —Br,—I, —CF₃, or —OCF₃.

In one embodiment, —R^(X2S), if present, is independently —F, —Cl, or—CF₃.

In one embodiment, —R^(X2S), if present, is independently —F or —Cl.

In one embodiment, —R^(X2S), if present, is independently —F.

In one embodiment, —R^(X2S), if present, is independently —Cl.

The Group —R^(X3S)

In one embodiment, —R^(X3S), if present, is independently —R^(X).

In one embodiment, —R^(X3S), if present, is independently —F, —Cl, —Br,—I, —R^(XA), —OR^(XA), —SR^(XA), —CF₃, or —OCF₃, wherein each —R^(XA) isindependently saturated aliphatic C₁₋₄alkyl.

In one embodiment, —R^(X3S), if present, is independently —F, —Cl, —Br,—I, —R^(XA), —OR^(XA), —CF₃, or —OCF₃.

In one embodiment, —R^(X3S), if present, is independently —F, —Cl, —Br,—I, —CF₃, or —OCF₃.

In one embodiment, —R^(X3S), if present, is independently —F, —Cl, or—CF₃.

In one embodiment, —R^(X3S), if present, is independently —F or —Cl.

In one embodiment, —R^(X3S), if present, is independently —F.

In one embodiment, —R^(X3S), if present, is independently —Cl.

The Group —R^(X4S)

In one embodiment, —R^(X4S), if present, is independently —R^(X).

In one embodiment, —R^(X4S), if present, is independently —F, —Cl, —Br,—I, —R^(XA), —OR^(XA), —SR^(XA), —CF₃, or —OCF₃, wherein each —R^(XA) isindependently saturated aliphatic C₁₋₄alkyl.

In one embodiment, —R^(X4S), if present, is independently —F, —Cl, —Br,—I, —R^(XA), —OR^(XA), —CF₃, or —OCF₃.

In one embodiment, —R^(X4S), if present, is independently —F, —Cl, —Br,—I, —CF₃, or —OCF₃.

In one embodiment, —R^(X4S), if present, is independently —F, —Cl, or—CF₃.

In one embodiment, —R^(X4S), if present, is independently —F or —Cl.

In one embodiment, —R^(X4S), if present, is independently —F.

In one embodiment, —R^(X4S), if present, is independently —Cl.

In one embodiment, —R^(X2S) and —R^(X4S), if present, are eachindependently —F.

In one embodiment, —R^(X2S) and —R^(X4S), if present, are eachindependently —Cl.

The Group —R^(XA)

In one embodiment, each —R^(XA), if present, is independently saturatedaliphatic C₁₋₄alkyl.

In one embodiment, each —R^(XA), if present, is independently -Me or-Et.

In one embodiment, each —R^(XA), if present, is independently -Me.

The Group -DQ

In embodiment, -DQ is independently -D¹-Q¹ or -D²=O.

In embodiment, -DQ is independently -D¹-Q¹.

In embodiment, -DQ is independently -D²=O.

The Group -D¹-

In one embodiment, -D¹-, if present, is independentlycyclopentane-di-yl, cyclohexane-di-yl, cycloheptane-di-yl,bicyclo[3.1.1]heptane-di-yl, or bicyclo[3.2.1]octane-di-yl, and isoptionally substituted with one or more groups —R^(D).

In one embodiment, -D¹-, if present, is independentlycyclopentane-di-yl, cyclohexane-di-yl, or cycloheptane-di-yl, and isoptionally substituted with one or more groups —R^(D).

In one embodiment, -D¹-, if present, is independentlycyclopentane-di-yl, cyclohexane-di-yl, cycloheptane-di-yl,bicyclo[3.1.1]heptane-di-yl, or bicyclo[3.2.1]octane-di-yl.

In one embodiment, -D¹-, if present, is independentlycyclopentane-di-yl, cyclohexane-di-yl, or cycloheptane-di-yl.

In one embodiment, -D¹-, if present, is independently cyclopentane-di-ylor cyclohexane-di-yl.

In one embodiment, -D¹-, if present, is independentlycyclopentane-di-yl.

In one embodiment, -D¹-, if present, is independentlycyclopentane-1,2-di-yl.

In one embodiment, -D¹-, if present, is independentlycyclopentane-1,3-di-yl.

In one embodiment, -D¹-, if present, is independently cyclohexane-di-yl.

In one embodiment, -D¹-, if present, is independentlycyclohexane-1,2-di-yl.

In one embodiment, -D¹-, if present, is independentlycyclohexane-1,3-di-yl.

In one embodiment, -D¹-, if present, is independentlycyclohexane-1,4-di-yl.

In one embodiment, -D¹-, if present, is independentlycycloheptane-di-yl.

In one embodiment, -D¹-, if present, is independentlycycloheptane-1,2-di-yl.

In one embodiment, -D¹-, if present, is independentlycycloheptane-1,3-di-yl.

In one embodiment, -D¹-, if present, is independentlycycloheptane-1,4-di-yl.

In one embodiment, -D¹-, if present, is independentlycyclopentane-1,2-di-yl, cyclopentane-1,3-di-yl, cyclohexane-1,3-di-yl,cyclohexane-1,4-di-yl, or cycloheptane-1,4-di-yl.

In one embodiment, -D¹-, if present, is independentlycyclopentane-1,2-di-yl, cyclopentane-1,3-di-yl, orcyclohexane-1,4-di-yl.

In one embodiment, -D¹-, if present, is independentlybicyclo[3.2.1]octane-di-yl.

In one embodiment, -D¹-, if present, is independentlybicyclo[3.2.1]octane-3,8-di-yl.

In one embodiment, -D¹-, if present, is independentlybicyclo[3.2.1]octane-8,3-di-yl.

In one embodiment, -D¹-, if present, is independentlybicyclo[3.1.1]heptane-di-yl.

In one embodiment, -D¹-, if present, is independentlybicyclo[3.1.1]heptane-3,6-di-yl.

In one embodiment, -D¹-, if present, is independentlybicyclo[3.1.1]heptane-6,3-di-yl.

For the avoidance of doubt, where no conformation is indicated, allpossible conformations are encompassed.

For example, the group described as:

encompasses (at least) the following well known conformations:

Similarly, the group described as:

encompasses (at least) the following well known conformations:

Similarly, the group described as:

encompasses (at least) the following well known conformations:

Similarly, the group described as:

encompasses (at least) the following well known conformations:

For example, the group described as:

encompasses (at least) the following well known conformations:

The Group -D²=

In one embodiment, -D²=, if present, is independentlycyclopentane-yl-ylidene, cyclohexane-yl-ylidene,cycloheptane-yl-ylidene, bicyclo[3.1.1]heptane-yl-ylidene, orbicyclo[3.2.1]octane-yl-ylidene, and is optionally substituted with oneor more groups —R^(D).

In one embodiment, -D²=, if present, is independentlycyclopentane-yl-ylidene, cyclohexane-yl-ylidene,cycloheptane-yl-ylidene, bicyclo[3.1.1]heptane-yl-ylidene, orbicyclo[3.2.1]octane-yl-ylidene.

In one embodiment, -D²=, if present, is independentlycyclopentane-yl-ylidene, cyclohexane-yl-ylidene, orcycloheptane-yl-ylidene, and is optionally substituted with one or moregroups —R^(D).

In one embodiment, -D²=, if present, is independentlycyclopentane-yl-ylidene, cyclohexane-yl-ylidene, orcycloheptane-yl-ylidene.

In one embodiment, -D²=, if present, is independentlycyclopentane-yl-ylidene or cyclohexane-yl-ylidene.

In one embodiment, -D²=, if present, is independentlycyclopentane-yl-ylidene.

In one embodiment, -D²=, if present, is independentlycyclopentane-1-yl-2-ylidine.

In one embodiment, -D²=, if present, is independentlycyclopentane-1-yl-3-ylidine.

In one embodiment, -D²=, if present, is independentlycyclohexane-yl-ylidene.

In one embodiment, -D²=, if present, is independentlycyclohexane-1-yl-2-ylidine.

In one embodiment, -D²=, if present, is independentlycyclohexane-1-yl-3-ylidine.

In one embodiment, -D²=, if present, is independentlycyclohexane-1-yl-4-ylidine.

In one embodiment, -D²=, if present, is independentlycycloheptane-yl-ylidene.

In one embodiment, -D²=, if present, is independentlycycloheptane-1-yl-2-ylidine.

In one embodiment, -D²=, if present, is independentlycycloheptane-1-yl-3-ylidine.

In one embodiment, -D²=, if present, is independentlycycloheptane-1-yl-4-ylidine.

In one embodiment, -D²=, if present, is independentlycyclohexane-1-yl-4-ylidine, and -D²=O is:

In one embodiment, -D²=, if present, is independentlybicyclo[3.2.1]octane-yl-ylidene.

In one embodiment, -D²=, if present, is independentlybicyclo[3.2.1]octane-3-yl-8-ylidene.

In one embodiment, -D²=, if present, is independentlybicyclo[3.2.1]octane-8-yl-3-ylidene.

In one embodiment, -D²=, if present, is independentlybicyclo[3.1.1]heptane-yl-ylidene.

In one embodiment, -D²=, if present, is independentlybicyclo[3.1.1]heptane-3-yl-6-ylidene.

In one embodiment, -D²=, if present, is independentlybicyclo[3.1.1]heptane-6-yl-3-ylidene.

Again, for the avoidance of doubt, where no conformation is indicated,all possible conformations are encompassed.

The Groups —R^(D)

In one embodiment, each —R^(D), if present, is independently selectedfrom —F, —Cl, —Br, —I, —R^(DD), —CF₃, —OH, —OR^(DD), —NH₂, —NHR^(DD),and —NR^(DD) ₂, wherein each —R^(DD) is independently saturatedaliphatic C₁₋₄alkyl.

In one embodiment, each —R^(DD), if present, is independently -Me or-Et.

In one embodiment, each —R^(DD), if present, is independently -Me.

For example, in one embodiment, -D¹-, if present, is independently4-methyl-cyclohexane-1,4-di-yl.

The Group -Q¹

In one embodiment, -Q¹, if present, is independently selected from:

In one embodiment, -Q¹, if present, is independently selected from:

In one embodiment, -Q¹, if present, is independently:

In one embodiment, -Q¹, if present, is independently:

In one embodiment, -Q¹, if present, is independently selected from:

In one embodiment, -Q¹, if present, is independently selected from:

In one embodiment, -Q¹, if present, is independently:

In one embodiment, -Q¹, if present, is independently:

In one embodiment, -Q¹, if present, is independently:

In one embodiment, -Q¹, if present, is independently selected from:

In one embodiment, -Q¹, if present, is independently selected from:

In one embodiment, -Q¹, if present, is independently:

In one embodiment, -Q¹, if present, is independently:

In one embodiment, -Q¹, if present, is independently:

For the avoidance of doubt, where no stereochemistry is indicated, allpossible conformations are encompassed.

For example, the group described as —CH(Me)OH or as any of thefollowing:

encompasses both stereoisomers:

The Groups —R^(1N) and —R^(2N)

In one embodiment:

-   -   each —R^(1N), if present, is independently —H, —R^(CN), or        —R^(CF);    -   each —R^(2N), if present, is independently —H, —R^(CN), or        —R^(CF);    -   each —R^(CN), if present, is independently saturated aliphatic        C₁₋₄alkyl; and    -   each —R^(CF), if present, is independently saturated aliphatic        C₁₋₄fluoroalkyl;    -   or:    -   —NR^(1N)R^(2N), if present, is independently azetidino,        pyrrolidino, imidazolidino, pyrazolidino, piperidino,        piperazino, morpholino, thiomorpholino, azepino, or diazepino,        each optionally substituted with one or more groups        independently selected from saturated aliphatic C₁₋₄alkyl.

In one embodiment:

-   -   each —R^(1N), if present, is independently —H or —R^(CN);    -   each —R^(2N), if present, is independently —H or —R^(CN); and    -   each —R^(CN), if present, is independently saturated aliphatic        C₁₋₄alkyl;    -   or:    -   —NR^(1N)R^(2N), if present, is independently azetidino,        pyrrolidino, imidazolidino, pyrazolidino, piperidino,        piperazino, morpholino, thiomorpholino, azepino, or diazepino,        each optionally substituted with one or more groups        independently selected from saturated aliphatic C₁₋₄alkyl.

In one embodiment:

-   -   each —R^(1N), if present, is independently —H, —R^(CN), or        —R^(CF); and    -   each —R^(2N), if present, is independently —H, —R^(CN), or        —R^(CF).

In one embodiment:

-   -   each —R^(1N), if present, is independently —H or —R^(CN); and    -   each —R^(2N), if present, is independently —H or —R^(CN).

In one embodiment:

-   -   each —R^(1N), if present, is independently —H, —R^(CN), or        —R^(CF); and    -   each —R^(2N), if present, is independently —H.

In one embodiment:

-   -   each —R^(1N), if present, is independently —H or —R^(CN); and    -   each —R^(2N), if present, is independently —H.

In one embodiment:

-   -   each —R^(1N), if present, is independently —R^(CN) or —R^(CF);        and    -   each —R^(2N), if present, is independently —H.

In one embodiment:

-   -   each —R^(1N), if present, is independently —R^(CN); and    -   each —R^(2N), if present, is independently —H.

In one embodiment:

-   -   each —R^(1N), if present, is independently —R^(CF); and    -   each —R^(2N), if present, is independently —H.

In one embodiment:

-   -   each —R^(1N), if present, is independently —R^(CN); and    -   each —R^(2N), if present, is independently —R^(CN).

In one embodiment:

-   -   each —R^(1N), if present, is independently —H; and    -   each —R^(2N), if present, is independently —H.

In one embodiment —NR^(1N)R^(2N), if present, is independentlyazetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino,piperazino, morpholino, thiomorpholino, azepino, or diazepino, eachoptionally substituted with one or more groups independently selectedfrom saturated aliphatic C₁₋₄alkyl.

In one embodiment, —NR^(1N)R^(2N), if present, is independentlypyrrolidino, piperidino, piperazino, or morpholino, each optionallysubstituted with one or more groups independently selected fromsaturated aliphatic C₁₋₄alkyl.

In one embodiment, —NR^(1N)R^(2N), if present, is independentlypiperidino, piperazino, or morpholino, each optionally substituted withone or more groups independently selected from saturated aliphaticC₁₋₄alkyl.

In one embodiment —NR^(1N)R^(2N), if present, is independentlypyrrolidino or morpholino.

In one embodiment —NR^(1N)R^(2N), if present, is independentlymorpholino.

In one embodiment, each —R^(CN), if present, is independently -Me or-Et.

In one embodiment, each —R^(CN), if present, is independently -Me.

In one embodiment, each —R^(CF), if present, is independently —CF₃,—CH₂CF₃, or —CH₂CH₂F.

In one embodiment, each —R^(CF), if present, is independently —CF₃.

In one embodiment, —NR^(1N)R^(2N), if present, is independently —NH₂,—NHMe, —NMe₂, —NHEt, —NEt₂, —NMeEt, —NH(iPr), —NH(CH₂CF₃), pyrrolidino,or morpholino.

In one embodiment, —NR^(1N)R^(2N), if present, is independently —NH₂,—NHMe, —NMe₂, or morpholino.

The Groups —R^(1A) and —R^(2A)

In one embodiment:

-   -   —R^(1A), if present, is independently —H, —R^(C), or —R^(F); and    -   —R^(2A), if present, is independently —H, —R^(C), or —R^(F);    -   or —R^(1A) and —R^(2A), if present, together form a saturated        aliphatic C₂₋₄alkylene group.

In one embodiment:

-   -   R^(1A), if present, is independently —H, —R^(C), or —R^(F); and    -   —R^(2A), if present, is independently —H, —R^(C), or —R^(F).

In one embodiment:

-   -   R^(1A), if present, is independently —H or —R^(C); and    -   —R^(2A), if present, is independently —H or —R^(C).

In one embodiment:

-   -   R^(1A), if present, is independently —H or —R^(C); and    -   —R^(2A), if present, is independently —H.

In one embodiment:

-   -   R^(1A), if present, is independently —R^(C); and    -   —R^(2A), if present, is independently —H.

In one embodiment:

-   -   R^(1A), if present, is independently —R^(C); and    -   —R^(2A), if present, is independently —R^(C).

In one embodiment:

-   -   —R^(1A), if present, is independently —H; and    -   —R^(2A), if present, is independently —H.

In one embodiment, —R^(1A) and —R^(2A), if present, together form asaturated aliphatic C₂₋₄alkylene group.

In one embodiment, —R^(1A) and —R^(2A), if present, together form—CH₂CH₂—, —CH₂CH₂CH₂—, or —CH₂CH₂CH₂CH₂—.

In one embodiment, —R^(1A) and —R^(2A), if present, together form—CH₂CH₂—.

The Groups —R^(1B) and —R^(2B)

In one embodiment:

-   -   —R^(1B) is independently —H, —R^(C), or —R^(F); and    -   —R^(2B) is independently —H, —R^(C), or —R^(F);    -   or —R^(1B) and —R^(2B) together form a saturated aliphatic        C₂₋₄alkylene group;    -   or —R^(1B) and —R^(2B) together form ═O.

In one embodiment:

-   -   —R^(1B), if present, is independently —H, —R^(C), or —R^(F); and    -   —R^(2B), if present, is independently —H, —R^(C), or —R^(F);    -   or —R^(1B) and —R^(2B), if present, together form a saturated        aliphatic C₂₋₄alkylene group.

In one embodiment:

-   -   —R^(1B), if present, is independently —H, —R^(C), or —R^(F); and    -   —R^(2B), if present, is independently —H, —R^(C), or —R^(F).

In one embodiment:

-   -   —R^(1B), if present, is independently —H or —R^(C); and    -   —R^(2B), if present, is independently —H or —R^(C).

In one embodiment:

-   -   —R^(1B), if present, is independently —H or —R^(C); and    -   —R^(2B), if present, is independently —H.

In one embodiment:

-   -   —R^(1B), if present, is independently —R^(C); and    -   —R^(2B), if present, is independently —H.

In one embodiment:

-   -   —R^(1B), if present, is independently —R^(C); and    -   —R^(2B), if present, is independently —R^(C).

In one embodiment:

-   -   —R^(1B), if present, is independently —H; and    -   —R^(2B), if present, is independently —H.

In one embodiment, —R^(1B) and —R^(2B), if present, together form asaturated aliphatic C₂₋₄alkylene group.

In one embodiment, —R^(1B) and —R^(2B), if present, together form—CH₂CH₂—, —CH₂CH₂CH₂—, or —CH₂CH₂CH₂CH₂—.

In one embodiment, —R^(1B) and —R^(2B), if present, together form—CH₂CH₂—.

In one embodiment, —R^(1B) and —R^(2B), if present, together form ═O.

The Groups —R^(3A) and —R^(4A)

In one embodiment:

-   -   —R^(3A), if present, is independently —H, —R^(C), or —R^(F); and    -   —R^(4A), if present, is independently —H, —R^(C), or —R^(F);    -   or —R^(3A) and —R^(4A), if present, together form a saturated        aliphatic C₂₋₄alkylene group.

In one embodiment:

—R^(3A), if present, is independently —H, —R^(C), or —R^(F); and

-   -   —R^(4A), if present, is independently —H, —R^(C), or —R^(F).

In one embodiment:

-   -   —R^(3A), if present, is independently —H or —R^(C); and    -   —R^(4A), if present, is independently —H or —R^(C).

In one embodiment:

-   -   —R^(3A), if present, is independently —H or —R^(C); and    -   —R^(4A), if present, is independently —H.

In one embodiment:

-   -   —R^(3A), if present, is independently —R^(C); and    -   —R^(4A), if present, is independently —H.

In one embodiment:

-   -   —R^(3A), if present, is independently —R^(C); and    -   —R^(4A), if present, is independently —R^(C).

In one embodiment:

-   -   —R^(3A), if present, is independently —H; and    -   —R^(4A), if present, is independently —H.

In one embodiment, —R^(3A) and —R^(4A), if present, together form asaturated aliphatic C₂₋₄alkylene group.

In one embodiment, —R^(3A) and —R^(4A), if present, together form—CH₂CH₂—, —CH₂CH₂CH₂—, or —CH₂CH₂CH₂CH₂—.

In one embodiment, —R^(3A) and —R^(4A), if present, together form—CH₂CH₂—.

The Groups —R^(5A) and —R^(6A)

In one embodiment:

-   -   —R^(5A), if present, is independently —H, —R^(C), —R^(F), or        —R^(J); and    -   —R^(6A), if present, is independently —H, —R^(C), or —R^(F);    -   or —R^(5A) and —R^(6A), if present, together form a saturated        aliphatic C₂₋₄alkylene group.

In one embodiment:

-   -   —R^(5A), if present, is independently —H, —R^(C), or —R^(J); and    -   —R^(6A), if present, is independently —H or —R^(C).

In one embodiment:

-   -   —R^(5A), if present, is independently —R^(J); and    -   —R^(6A), if present, is independently —H or —R^(C).

In one embodiment:

-   -   —R^(5A), if present, is independently —R^(J); and    -   —R^(6A), if present, is independently —H.

In one embodiment:

-   -   —R^(5A), if present, is independently —R^(J); and    -   —R^(6A), if present, is independently —R^(C).

In one embodiment:

-   -   —R^(5A), if present, is independently —H or —R^(C); and    -   —R^(6A), if present, is independently —H or —R^(C).

In one embodiment:

-   -   —R^(5A), if present, is independently —H or —R^(C); and    -   —R^(6A), if present, is independently —H.

In one embodiment:

-   -   —R^(5A), if present, is independently —R^(C); and    -   —R^(6A), if present, is independently —H.

In one embodiment:

-   -   —R^(5A), if present, is independently —R^(C); and    -   —R^(6A), if present, is independently —R^(C).

In one embodiment:

-   -   —R^(5A), if present, is independently —H; and    -   —R^(6A), if present, is independently —H.

In one embodiment, —R^(5A) and —R^(6A), if present, together form asaturated aliphatic C₂₋₄alkylene group.

In one embodiment, —R^(5A) and —R^(6A), if present, together form—CH₂CH₂—, —CH₂CH₂CH₂—, or —CH₂CH₂CH₂CH₂—.

In one embodiment, —R^(5A) and —R^(6A), if present, together form—CH₂CH₂—.

The Groups —R^(3B) and —R^(4B)

In one embodiment:

-   -   —R^(3B), if present, is independently —H, —R^(C), or —R^(F); and    -   —R^(4B), if present, is independently —H, —R^(C), or —R^(F);    -   or —R^(3B) and —R^(4B), if present, together form a saturated        aliphatic C₂₋₄alkylene group.

In one embodiment:

-   -   —R^(3B), if present, is independently —H, —R^(C), or —R^(F); and    -   —R^(4B), if present, is independently —H, —R^(C), or —R^(F).

In one embodiment:

-   -   —R^(3B), if present, is independently —H or —R^(C); and    -   —R^(4B), if present, is independently —H or —R^(C).

In one embodiment:

-   -   —R^(3B), if present, is independently —H or —R^(C); and    -   —R^(4B), if present, is independently —H.

In one embodiment:

-   -   —R^(3B), if present, is independently —R^(C); and    -   —R^(4B), if present, is independently —H.

In one embodiment:

-   -   —R^(3B), if present, is independently —R^(C); and    -   —R^(4B), if present, is independently —R^(C).

In one embodiment:

-   -   —R^(3B), if present, is independently —H; and    -   —R^(4B), if present, is independently —H.

In one embodiment, —R^(3B) and —R^(4B), if present, together form asaturated aliphatic C₂₋₄alkylene group.

In one embodiment, —R^(3B) and —R^(4B), if present, together form—CH₂CH₂—, —CH₂CH₂CH₂—, or —CH₂CH₂CH₂CH₂—.

In one embodiment, —R^(3B) and —R^(4B), if present, together form—CH₂CH₂—.

The Groups —R^(5B) and —R^(6B)

In one embodiment:

-   -   —R^(5B), if present, is independently —H, —R^(C), —R^(F), —OH,        or —OR^(O); and    -   —R^(6B), if present, is independently —H, —R^(C), or —R^(F);    -   or —R^(5B) and —R^(6B), if present, together form a saturated        aliphatic C₂₋₄alkylene group.

In one embodiment:

-   -   —R^(5B), if present, is independently —H, —R^(C), —R^(F), —OH,        or —OR^(O) and    -   —R^(6B), if present, is independently —H, —R^(C), or —R^(F).

In one embodiment:

-   -   —R^(5B), if present, is independently —H, —R^(C), —OH, or        —OR^(O); and    -   —R^(6B), if present, is independently —H or —R^(C).

In one embodiment:

-   -   —R^(5B), if present, is independently —OH or —OR^(O); and    -   —R^(6B), if present, is independently —H or —R^(C).

In one embodiment:

-   -   —R^(5B), if present, is independently —OH or —OR^(O); and    -   if present, is independently —H.

In one embodiment:

-   -   —R^(5B), if present, is independently —OH; and    -   —R^(6B), if present, is independently —H.

In one embodiment:

-   -   —R^(5B), if present, is independently —H or —R^(C); and    -   —R^(6B), if present, is independently —H or —R^(C).

In one embodiment:

-   -   —R^(5B), if present, is independently —H or —R^(C); and    -   —R^(6B), if present, is independently —H.

In one embodiment:

-   -   —R^(5B), if present, is independently —H; and    -   —R^(6B), if present, is independently —R^(C).

In one embodiment:

-   -   —R^(5B), if present, is independently —R^(C); and    -   —R^(6B), if present, is independently —R^(C).

In one embodiment:

-   -   —R^(5B), if present, is independently —H; and    -   —R^(6B), if present, is independently —H.

In one embodiment, —R^(5B) and —R^(6B), if present, together form asaturated aliphatic C₂₋₄alkylene group.

In one embodiment, —R^(5B) and —R^(6B), if present, together form—CH₂CH₂—, —CH₂CH₂CH₂—, or —CH₂CH₂CH₂CH₂—.

In one embodiment, —R^(5B) and —R^(6B), if present, together form—CH₂CH₂—.

The Group —R^(O)

In one embodiment, —R^(O), if present, is independently saturatedaliphatic C₁₋₄alkyl.

In one embodiment, —R^(O), if present, is independently -Me or -Et.

In one embodiment, —R^(O), if present, is independently -Me.

The Group —R^(C)

In one embodiment, each —R^(C), if present, is independently saturatedaliphatic C₁₋₄alkyl.

In one embodiment, each —R^(C), if present, is independently -Me or -Et.

In one embodiment, each —R^(C), if present, is independently -Me.

The Group —R^(F)

In one embodiment, each —R^(F), if present, is independently saturatedaliphatic C₁₋₄fluoroalkyl.

In one embodiment, each —R^(F), if present, is independently —CF₃,—CH₂CF₃, or —CH₂CH₂F.

In one embodiment, each —R^(F), if present, is independently —CF₃.

The Group —R^(J)

In one embodiment, —R^(J), if present, is independently —NH₂,—NHR^(JN1), —NR^(JN1) ₂, or —NR^(JN2)R^(JN3).

In one embodiment, —R^(J), if present, is independently —NH₂,—NHR^(JN1), or —NR^(JN1) ₂.

In one embodiment, —R^(J), if present, is independently —NH₂.

In one embodiment, —R^(J), if present, is independently —NHR^(JN1).

In one embodiment, —R^(J), if present, is independently —NR^(JN1) ₂.

In one embodiment, —R^(J), if present, is independently—NR^(JN2)R^(JN3).

In one embodiment, each —R^(JN1), if present, is independently saturatedaliphatic C₁₋₄alkyl.

In one embodiment, each —R^(JN1), if present, is independently -Me, -Et,or -iPr.

In one embodiment, each —R^(JN1), if present, is independently -Me or-Et.

In one embodiment, each —R^(JN1), if present, is independently -Me.

In one embodiment, —NR^(JN2)R^(JN3), if present, is independentlyazetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino,piperazino, morpholino, thiomorpholino, azepino, or diazepino, eachoptionally substituted with one or more groups independently selectedfrom saturated aliphatic C₁₋₄alkyl.

In one embodiment, —NR^(JN2)R^(JN3), if present, is independentlypiperidino, piperazino, or morpholino, each optionally substituted withone or more groups independently selected from saturated aliphaticC₁₋₄alkyl.

In one embodiment, —NR^(JN2)R^(JN3), if present, is independentlymorpholino.

In one embodiment, —R^(J), if present, is independently —NH₂, —NHMe,—NMe₂, —NHEt, —NEt₂, —NH(nPr), —N(nPr)₂, —NH(iPr), —N(iPr)₂, piperidino,piperazino, or morpholino.

In one embodiment, —R^(J), if present, is independently —NH₂, —NHMe,—NMe₂, or morpholino.

In one embodiment, —R^(J), if present, is independently —NH₂, —NHMe, or—NMe₂.

The Group -Q¹: Some Preferred Embodiments

In one embodiment, -Q¹, if present, is independently —OH, —CH₂OH,—CH(Me)OH, —C(Me)₂OH, —NH₂, —NHMe, —NMe₂, —NHEt, —NEt₂, —NMeEt,—NH(iPr), pyrrolidino, morpholino, —NHCH₂CF₃, —CH₂NH₂, —CH₂NHMe,—CH₂NMe₂, —CH₂NHEt, —CH₂NEt₂, —CH(NHMe)CH₂OH, —C(═O)NH₂, —C(═O)NHMe,—C(═O)NMe₂, —C(═O)NHEt, or —C(═O)NEt₂.

In one embodiment, -Q¹, if present, is independently —OH, —CH₂OH,—CH(Me)OH, —C(Me)₂OH, —NH₂, —NHMe, —NMe₂, —NHEt, —NEt₂, or—CH(NHMe)CH₂OH.

In one embodiment, -Q¹, if present, is independently —OH, —CH₂OH,—CH(Me)OH, or —C(Me)₂OH.

In one embodiment, -Q¹, if present, is independently —OH.

In one embodiment, -Q¹, if present, is independently —CH₂OH, —CH(Me)OH,or —C(Me)₂OH.

In one embodiment, -Q¹, if present, is independently —CH₂OH.

In one embodiment, -Q¹, if present, is independently —NH₂, —NHMe, —NMe₂,—NHEt, —NEt₂, —NMeEt, —NH(iPr), pyrrolidino, morpholino, —NHCH₂CF₃,—CH₂NH₂, —CH₂NHMe, —CH₂NMe₂, —CH₂NHEt, —CH₂NEt₂, —CH(NHMe)CH₂OH,—C(═O)NH₂, —C(═O)NHMe, —C(═O)NMe₂, —C(═O)NHEt, or —C(═O)NEt₂.

In one embodiment, -Q¹, if present, is independently —NH₂, —NHMe, —NMe₂,—NHEt, —NEt₂, —NMeEt, —NH(iPr), pyrrolidino, morpholino, —NHCH₂CF₃,—CH₂NH₂, —CH₂NHMe, —CH₂NMe₂, —CH₂NHEt, —CH₂NEt₂, or —CH(NHMe)CH₂OH.

In one embodiment, -Q¹, if present, is independently —NH₂, —NHMe, —NMe₂,—NHEt, or —NEt₂.

The Group —R^(SN)

In one embodiment, —R^(SN) is independently —H or saturated aliphaticC₁₋₄alkyl.

In one embodiment, —R^(SN) is independently —H, -Me, or -Et.

In one embodiment, —R^(SN) is independently —H.

Some Preferred Combinations

In one preferred embodiment:

-   -   -A is independently:

-   -   -DQ is independently -D¹-Q¹;    -   -D¹- is independently cyclopentane-di-yl or cyclohexane-di-yl.

In one preferred embodiment:

-   -   -A is independently:

-   -   -DQ is independently -D¹-Q¹;    -   -D¹- is independently cyclopentane-di-yl or cyclohexane-di-yl;        and    -   -Q¹ is independently —OH, —CH₂OH, —CH(Me)OH, —C(Me)₂OH, —NH₂,        —NHMe, —NMe₂, —NHEt, —NEt₂, or —CH(NHMe)CH₂OH.

In one preferred embodiment:

-   -   -A is independently:

-   -   -DQ is independently -D¹-Q¹;    -   -D¹- is independently cyclopentane-di-yl or cyclohexane-di-yl;        and    -   -Q¹ is independently —OH.

In one preferred embodiment:

-   -   -A is independently:

-   -   -DQ is independently -D¹-Q¹;    -   -D¹- is independently cyclohexane-di-yl; and    -   -Q¹ is independently —OH.

In one preferred embodiment:

-   -   -A is independently:

-   -   -DQ is independently -D¹-Q¹;    -   -D¹- is independently cyclopentane-di-yl or cyclohexane-di-yl;        and    -   -Q¹ is independently —CH₂OH, —CH(Me)OH, or —C(Me)₂OH.

In one preferred embodiment:

-   -   -A is independently:

-   -   -DQ is independently -D¹-Q¹;    -   -D¹- is independently cyclopentane-di-yl or cyclohexane-di-yl;        and    -   -Q¹ is independently —CH₂OH.

In one preferred embodiment:

-   -   -A is independently:

-   -   -DQ is independently -D¹-Q¹;    -   -D¹- is independently cyclopentane-di-yl or cyclohexane-di-yl;        and    -   -Q¹ is independently —NH₂, —NHMe, —NMe₂, —NHEt, —NEt₂.

In one preferred embodiment:

-   -   -A is independently:

-   -   -DQ is independently -D¹-Q¹;    -   -D¹- is independently cyclopentane-di-yl or cyclohexane-di-yl;        and    -   -Q¹ is independently —CH(NHMe)CH₂OH.

In other preferred embodiments, additionally:

-   -   —R^(X2) is independently —F or —Cl; and    -   —R^(X4) is independently —F or —Cl.

In other preferred embodiments, additionally:

-   -   —R^(X2) is independently —F or —Cl;    -   —R^(X4) is independently —F or —Cl; and    -   —R^(SN) is independently —H or -Me.

In other preferred embodiments, additionally:

-   -   —R^(X2) is independently —F;    -   —R^(X4) is independently —F; and    -   —R^(SN) is independently —H.

In other preferred embodiments, additionally, —R^(J), if present, isindependently —NH₂, —NHMe, —NMe₂, —NHEt, —NEt₂, —NH(nPr), —N(nPr)₂,—NH(iPr), —N(iPr)₂, piperidino, piperazino, or morpholino.

In other preferred embodiments, additionally, —R^(J), if present, isindependently —NH₂, —NHMe, —NMe₂, or morpholino.

In other preferred embodiments, additionally, —R^(J), if present, isindependently —NH₂, —NHMe, or —NMe₂.

Molecular Weight

In one embodiment, the APSAC compound has a molecular weight of from 317to 1200.

In one embodiment, the bottom of range is 325, 350, 375, 400, 425, 450,500.

In one embodiment, the top of range is 1100, 1000, 900, 800, 700, or600.

In one embodiment, the range is from 350 to 700.

Combinations

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention, which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable sub-combination. All combinations of the embodimentspertaining to the chemical groups represented by the variables (e.g.,-A, —Ar, p, —R^(X), q, —R^(SN), -D^(Q), -D¹-, -Q¹, -D²=, —R^(D),—R^(DD), —R^(1A), —R^(2A), —R^(3A), —R^(4A), —R^(5A), —R^(6A), —R^(1B),—R^(2B), —R^(3B), —R^(4B), —R^(5B), —R^(6B), —R^(1N), —R^(2N), —R^(CN),—R^(CF), —NR^(1N)R^(2N), —R^(C), —R^(F), —R^(J), —R^(O), —R^(JN1),—NR^(JN2)R^(JN3), —R^(XX), —NR^(YY)R^(ZZ), —R^(XXX), ═W—, —Y═, —R^(W),—R^(Y), —R^(X2), —R^(X3), —R^(X4), —R^(X2S), —R^(X3S), —R^(X4S),—R^(XA), etc.) are specifically embraced by the present invention andare disclosed herein just as if each and every combination wasindividually and explicitly disclosed, to the extent that suchcombinations embrace compounds that are stable compounds (i.e.,compounds that can be isolated, characterised, and tested for biologicalactivity). In addition, all sub-combinations of the chemical groupslisted in the embodiments describing such variables are alsospecifically embraced by the present invention and are disclosed hereinjust as if each and every such sub-combination of chemical groups wasindividually and explicitly disclosed herein.

Specific Embodiments

In one embodiment, the compounds are selected from compounds of thefollowing formulae and pharmaceutically acceptable salts, hydrates, andsolvates thereof:

Compound No. Structure ABD599

ABD655

ABD665

ABD679

ABD682

ABD683

ABD684

ABD698

ABD699

ABD702

ABD703

ABD704

ABD705

ABD706

ABD710

ABD712

ABD714

ABD716

ABD730

ABD732

ABD735

ABD742

ABD756

ABD777

ABD827

ABD828

ABD836

ABD837

ABD839

ABD845

ABD861

In one embodiment, the compounds are selected from compounds of thefollowing formulae and pharmaceutically acceptable salts, hydrates, andsolvates thereof:

Compound No. Structure ABD769

ABD770

ABD771

ABD772

ABD773

ABD774

ABD775

ABD776

ABD781

ABD794

ABD795

ABD796

ABD797

ABD813

ABD814

ABD815

ABD840

ABD841

ABD846

ABD863

In one embodiment, the compounds are selected from compounds of thefollowing formulae and pharmaceutically acceptable salts, hydrates, andsolvates thereof:

Compound No Structure ABD787

ABD798

ABD799

ABD812

ABD816

ABD817

ABD818

ABD819

ABD820

ABD821

ABD822

ABD864

ABD865

In one embodiment, the compounds are selected from compounds of thefollowing formulae and pharmaceutically acceptable salts, hydrates, andsolvates thereof:

Compound No. Structure ABD823

ABD824

ABD825

ABD826

In one embodiment, the compounds are selected from compounds of thefollowing formulae and pharmaceutically acceptable salts, hydrates, andsolvates thereof:

Compound No. Structure ABD800

ABD842

ABD843

ABD844

In one embodiment, the compounds are selected from a compound of thefollowing formula and pharmaceutically acceptable salts, hydrates, andsolvates thereof:

Compound No. Structure ABD786

In one embodiment, the compounds are selected from compounds of thefollowing formulae and pharmaceutically acceptable salts, hydrates, andsolvates thereof:

Compound No. Structure ABD824a

ABD826a

ABD847

ABD848

ABD849

ABD868

In one embodiment, the compounds are selected from compounds of thefollowing formulae and pharmaceutically acceptable salts, hydrates, andsolvates thereof:

Compound No. Structure ABD899

ABD900

ABD901

ABD903

In one embodiment, the compounds is selected from a compound of thefollowing formula and pharmaceutically acceptable salts, hydrates, andsolvates thereof:

Compound No. Structure ABD902

Chirality

In some embodiments (for example, according to the choice for -D¹-; thechoices for —R^(1A) and —R^(2A); the choices for —R^(3A) and —R^(4A);the choices for —R^(5A) and —R^(6A); the choices for —R^(1B) and—R^(2B); the choices for —R^(3B) and —R^(4B); the choices for —R^(5B)and —R^(6B)), the compound may have one or more chiral centres.

The chiral centre, or each chiral centre, if more than one is present,is independently in the R-configuration or the S-configuration.

If no configuration is indicated, then both configurations areencompassed.

Substantially Purified Forms

One aspect of the present invention pertains to APSAC compounds, asdescribed herein, in substantially purified form and/or in a formsubstantially free from contaminants.

In one embodiment, the substantially purified form is at least 50% byweight, e.g., at least 60% by weight, e.g., at least 70% by weight,e.g., at least 80% by weight, e.g., at least 90% by weight, e.g., atleast 95% by weight, e.g., at least 97% by weight, e.g., at least 98% byweight, e.g., at least 99% by weight.

Unless specified, the substantially purified form refers to the compoundin any stereoisomeric or enantiomeric form. For example, in oneembodiment, the substantially purified form refers to a mixture ofstereoisomers, i.e., purified with respect to other compounds. In oneembodiment, the substantially purified form refers to one stereoisomer,e.g., optically pure stereoisomer. In one embodiment, the substantiallypurified form refers to a mixture of enantiomers. In one embodiment, thesubstantially purified form refers to an equimolar mixture ofenantiomers (i.e., a racemic mixture, a racemate). In one embodiment,the substantially purified form refers to one enantiomer, e.g.,optically pure enantiomer.

In one embodiment, the contaminants represent no more than 50% byweight, e.g., no more than 40% by weight, e.g., no more than 30% byweight, e.g., no more than 20% by weight, e.g., no more than 10% byweight, e.g., no more than 5% by weight, e.g., no more than 3% byweight, e.g., no more than 2% by weight, e.g., no more than 1% byweight.

Unless specified, the contaminants refer to other compounds, that is,other than stereoisomers or enantiomers. In one embodiment, thecontaminants refer to other compounds and other stereoisomers. In oneembodiment, the contaminants refer to other compounds and the otherenantiomer.

In one embodiment, the substantially purified form is at least 60%optically pure (i.e., 60% of the compound, on a molar basis, is thedesired stereoisomer or enantiomer, and 40% is the undesiredstereoisomer or enantiomer), e.g., at least 70% optically pure, e.g., atleast 80% optically pure, e.g., at least 90% optically pure, e.g., atleast 95% optically pure, e.g., at least 97% optically pure, e.g., atleast 98% optically pure, e.g., at least 99% optically pure.

Isomers

Certain compounds may exist in one or more particular geometric,optical, enantiomeric, diasteriomeric, epimeric, atropic,stereoisomeric, tautomeric, conformational, or anomeric forms, includingbut not limited to, cis- and trans-forms; E- and Z-forms; c-, t-, andr-forms; endo- and exo-forms; R-, S-, and meso-forms; D- and L-forms; d-and l-forms; (+) and (−) forms; keto-, enol-, and enolate-forms; syn-and anti-forms; synclinal- and anticlinal-forms; α- and β-forms; axialand equatorial forms; boat-, chair-, twist-, envelope-, andhalfchair-forms; and combinations thereof, hereinafter collectivelyreferred to as “isomers” (or “isomeric forms”).

Note that, except as discussed below for tautomeric forms, specificallyexcluded from the term “isomers,” as used herein, are structural (orconstitutional) isomers (i.e., isomers which differ in the connectionsbetween atoms rather than merely by the position of atoms in space). Forexample, a reference to a methoxy group, —OCH₃, is not to be construedas a reference to its structural isomer, a hydroxymethyl group, —CH₂OH.Similarly, a reference to ortho-chlorophenyl is not to be construed as areference to its structural isomer, meta-chlorophenyl. However, areference to a class of structures may well include structurallyisomeric forms falling within that class (e.g., C₁₋₇alkyl includesn-propyl and iso-propyl; butyl includes n-, iso-, sec-, and tert-butyl;methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl).

The above exclusion does not pertain to tautomeric forms, for example,keto-, enol-, and enolate-forms, as in, for example, the followingtautomeric pairs: keto/enol (illustrated below), imine/enamine,amide/imino alcohol, amidine/amidine, nitroso/oxime,thioketone/enethiol, N-nitroso/hydroxyazo, and nitro/aci-nitro.

Note that specifically included in the term “isomer” are compounds withone or more isotopic substitutions. For example, H may be in anyisotopic form, including ¹H, ²H (D), and ³H (T); C may be in anyisotopic form, including ¹²C, ¹³C, and ¹⁴C; O may be in any isotopicform, including ¹⁶O and ¹⁸O; and the like.

Unless otherwise specified, a reference to a particular compoundincludes all such isomeric forms, including mixtures (e.g., racemicmixtures) thereof. Methods for the preparation (e.g., asymmetricsynthesis) and separation (e.g., fractional crystallisation andchromatographic means) of such isomeric forms are either known in theart or are readily obtained by adapting the methods taught herein, orknown methods, in a known manner.

Salts

It may be convenient or desirable to prepare, purify, and/or handle acorresponding salt of the compound, for example, apharmaceutically-acceptable salt. Examples of pharmaceuticallyacceptable salts are discussed in Berge et al., 1977, “PharmaceuticallyAcceptable Salts,” J. Pharm. Sci., Vol. 66, pp. 1-19.

For example, if the compound is anionic, or has a functional group whichmay be anionic (e.g., —COOH may be —COO⁻), then a salt may be formedwith a suitable cation. Examples of suitable inorganic cations include,but are not limited to, alkali metal ions such as Na⁺ and K⁺, alkalineearth cations such as Ca²⁺ and Mg²⁺, and other cations such as Al⁺³.Examples of suitable organic cations include, but are not limited to,ammonium ion (i.e., NH₄ ⁺) and substituted ammonium ions (e.g., NH₃R⁺,NH₂R₂ ⁺, NHR₃ ⁺, NR₄ ⁺). Examples of some suitable substituted ammoniumions are those derived from: ethylamine, diethylamine,dicyclohexylamine, triethylamine, butylamine, ethylenediamine,ethanolamine, diethanolamine, piperazine, benzylamine,phenylbenzylamine, choline, meglumine, and tromethamine, as well asamino acids, such as lysine and arginine. An example of a commonquaternary ammonium ion is N(CH₃)₄ ⁺.

If the compound is cationic, or has a functional group which may becationic (e.g., —NH₂ may be —NH₃ ⁺), then a salt may be formed with asuitable anion. Examples of suitable inorganic anions include, but arenot limited to, those derived from the following inorganic acids:hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric,nitrous, phosphoric, and phosphorous.

Examples of suitable organic anions include, but are not limited to,those derived from the following organic acids: 2-acetyoxybenzoic,acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric,edetic, ethanedisulfonic, ethanesulfonic, fumaric, glucheptonic,gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalenecarboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic,methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic,phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic,succinic, sulfanilic, tartaric, toluenesulfonic, and valeric. Examplesof suitable polymeric organic anions include, but are not limited to,those derived from the following polymeric acids: tannic acid,carboxymethyl cellulose.

Unless otherwise specified, a reference to a particular compound alsoincludes salt forms thereof.

Solvates and Hydrates

It may be convenient or desirable to prepare, purify, and/or handle acorresponding solvate of the compound. The term “solvate” is used hereinin the conventional sense to refer to a complex of solute (e.g.,compound, salt of compound) and solvent. If the solvent is water, thesolvate may be conveniently referred to as a hydrate, for example, amono-hydrate, a di-hydrate, a tri-hydrate, etc.

Unless otherwise specified, a reference to a particular compound alsoincludes solvate and hydrate forms thereof.

Chemical Synthesis

Methods for the chemical synthesis of APSAC compounds of the presentinvention are described herein. These and/or other well-known methodsmay be modified and/or adapted in known ways in order to facilitate thesynthesis of additional APSAC compounds of the present invention.

In one approach, an appropriate biphenyl compound is prepared from aboronic acid and bromobenzene via a Suzuki coupling, for example, asdescribed by O'Brien et al., 2000. The biphenyl is sulfonylated usingchlorosulfonic acid to give the corresponding sulfonic acid. The acid isthen reacted with thionyl chloride to give the corresponding arylsulfonyl chloride. Finally the sulfonyl chloride is coupled with anamine to give the corresponding sulfonamide. An example of such a methodis shown in the following scheme.

In another approach, the sulfonamide can be formed first, from asuitable bromobenzene sulfonyl chloride and amine, and the biphenylcompound then prepared by a similar Suzuki methodology. An example ofsuch a method is shown in the following scheme.

In another approach, the cyclohexanol can be replaced by a cyclohexanemethyl alcohol, by coupling of the sulfonyl chloride with a carboxylicester and subsequent reduction. For example the biphenyl sulfonylchloride can be reacted with 4-amino-cyclohexane-carboxylic acid methylester in a solvent, such as DCM, in the presence of a suitable base,such as pyridine, and then reduced, for example, with lithium aluminiumhydride in a solvent, such as THF, to give the desired alcohol. Anexample of such a method is shown in the following scheme.

In another approach, the cyclohexane moiety can be replaced by othercarbocycles to give a range of target compounds. For example, each ofthe four isomers of 3-amino-cyclopentane carboxylic acid and each of thefour isomers of 3-amino-cyclopentane acetic acid are known and availableand can be coupled with the required sulfonyl chloride and subsequentlyreduced, for example, with lithium aluminium hydride, to give thedesired alcohol. Examples of such methods are shown in the followingschemes.

In another approach, the alcohol can be replaced by an amide by directreaction of the sulfonyl chloride with the required aminocarboxylicacid, subsequent chlorination of the acid, and coupling with therequired amine. For example, a biphenylsulfonyl chloride can be coupledwith 4-aminocyclohexane carboxylic acid in a solvent, such as DCM, inthe presence of a base, such as pyridine, the acid chlorinated by refluxin thionyl chloride, in a solvent such as DCM, and then coupled withmethylamine in a solvent such as THF. An example of such a method isshown in the following scheme.

In another approach, the amide is reduced to the corresponding amine byreaction with a suitable reducing agent. For example, the amide can bereduced by lithium aluminium hydride in a solvent such as THF. Anexample of such a method is shown in the following scheme.

In another approach, the amino group can be introduced by directreaction of a suitable amine with a sulfonyl chloride. For example abiphenyl sulfonyl chloride can be coupled with 1,4-diaminocyclohexane ina solvent, such as DCM, in the presence of a suitable base, such aspyridine. An example of such a method is shown in the following scheme.

In another approach, amino substitutions may be made by nucleophilicattack of a suitable amine on a cyclohexanone. For example, thecyclohexanone can be prepared from the cyclohexanol derivative by use ofJones' oxidation (chromium trioxide/sulfuric acid), subsequent reactionwith methylamine, and reduction in the presence of sodiumcyanoborohydride or sodium triacetoxyborohydride in a solvent, such asmethanol or THF. This methodology gives a mixture of products, which canbe separated by HPLC. An example of such a method is shown in thefollowing scheme.

In another approach, where direct amination of the cyclohexanone givesmultiple reactions, it is also possible to first react the ketone with2,4-dimethoxybenzylamine, to give a protected intermediate. Thisintermediate then releases the desired amine on treatment withtrifluoroacetic acid. An example of such a method is shown in thefollowing scheme.

In another approach, further substituents can be added to the amine. Forexample the amine can be reacted with an acid chloride or anhydride, togive an amide, which may then be further reduced to give the secondaryamine. For example, the amine can be acylated with trifluoroaceticanhydride in the presence of triethylamine and then reduced with boranein a solvent such as THF. The mixture of products may then be separatedby preparative HPLC to give the cis- and trans-isomers. An example ofsuch a method is shown in the following scheme.

In another approach, the cyclohexanone intermediate can be used toprepare cis- or trans-isomers where the required starting material isunavailable. For example, the cyclohexanone derivative can be preparedfrom trans-4-aminocyclohexanol and reduced with LS-Selectride (lithiumtrisiamylborohydride) in THF to give the cis-isomer as the finalproduct. An example of such a method is shown in the following scheme.

In another approach, the cyclohexanone intermediate can be reduced witha Grignard reagent to give the tertiary alcohol. For example, thecyclohexanone can be reacted with methyl magnesium bromide and theracemic mixture separated by preparative HPLC to give the cis- andtrans-isomers. An example of such a method is shown in the followingscheme.

In another approach, the cis and trans-aminocyclohexanol isomers can beseparated prior to coupling with the sulfonyl chloride. For example,trans-4-aminocyclohexanol can be amino-protected with a suitableprotecting group, oxidised to the cyclohexanone, reacted with a suitableGrignard, and then separated, prior to deprotection and coupling. Forexample, the amine can be BOC protected, using di-tert-butyldicarbonate, the alcohol oxidised using pyridinium chlorochromate, thecyclohexanone reacted with methylmagnesium chloride and the BOCprotecting group removed with a reagent such as trifluoroacetic acid orethanolic HCl, following separation of the isomers by columnchromatography. An example of such a method is shown in the followingscheme.

In another approach, further substituents may be added to a cyclohexaneor cyclopentane methylalcohol derivative, by nucleophilic attack on thecorresponding carboxylic ester. For example the ester can be reactedwith a Grignard reagent such as methyl magnesium bromide in a solventsuch as THF. An example of such a method is shown in the followingscheme.

In another approach, the biphenyl sulfonamide group can be replaced by aheteroaryl-phenyl sulfonamide motif by preparation of any of the abovederivatives as a bromophenyl sulfonamide derivative, preparation of theboronic acid or boronate, and subsequent Suzuki coupling with asubstituted pyridyl bromide, at a suitable stage of the reactionpathway. For example, bromobenzene sulfonamide compounds can be preparedfrom the cyclohexanol, cyclohexane carboxylic acid, and cyclopentanecarboxylic acid compounds described in the above schemes. These can thenbe reacted with bis(pinacolato)diboron to give the required borane,which can then be coupled with an appropriate heterocyclic bromide usingSuzuki coupling. Examples of such methods are shown in the followingschemes.

In another approach, all four 2-aminocyclopentane carboxylate isomerscan be prepared by reductive amination of ethyl2-oxocyclopentanecarboxylate and used to prepare the respectivesulfonamide-cyclopentane methyl alcohol compound. For example, ethyl2-oxocyclopentanecarboxylate can be reacted with ammonium acetate andthen reduced with sodium triacetoxyborohydride to give the racemicmixture of 2-aminocarboxylates, which may be separated by HPLC, orfurther coupled with a biphenyl sulfonyl chloride, reduced with lithiumaluminium hydride and then separated. An example is shown in thefollowing scheme.

Compositions

One aspect of the present invention pertains to a composition (e.g., apharmaceutical composition) comprising an APSAC compound, as describedherein, and a pharmaceutically acceptable carrier, diluent, orexcipient.

Another aspect of the present invention pertains to a method ofpreparing a composition (e.g., a pharmaceutical composition) comprisingadmixing an APSAC compound, as described herein, and a pharmaceuticallyacceptable carrier, diluent, or excipient.

Uses

The APSAC compounds described herein are believed to beanti-inflammatory agents, which may act by blockade or modification ofpro-inflammatory signalling pathways (for example those mediated by TNFαsignalling and NFκB or AP-1 activation) and thus may preventinflammation or suppress autoimmune responses or offer protectionagainst joint destruction and other effects of chronic inflammatorydisease.

The APSAC compounds described herein are also believed to beanti-resorptive agents, which may act by blockade or modification ofpathways that lead to excessive osteoclast activity (for example thosemediated by RANKL, TNFα, and IL-1 signalling and NFκB activation) andthereby protect against the bone loss seen in osteoporosis and manychronic inflammatory conditions.

Thus, the APSAC compounds described herein are believed to be useful inthe treatment of inflammation and/or joint destruction and/or bone loss.

Thus, the APSAC compounds described herein are believed to be useful inthe treatment of disorders mediated by excessive and/or inappropriateand/or prolonged activation of the immune system.

Thus, the APSAC compounds described herein are believed to be useful inthe treatment of, inflammatory and autoimmune disorders, for example,rheumatoid arthritis, psoriasis, psoriatic arthritis, chronicobstructive pulmonary disease (COPD), atherosclerosis, inflammatorybowel disease, ankylosing spondylitis, and the like.

Thus, the APSAC compounds described herein are believed to be useful inthe treatment of disorders associated with bone loss, such as bone lossassociated with excessive osteoclast activation in rheumatoid arthritis;osteoporosis; cancer-associated bone disease; Paget's disease; and thelike.

Thus, the APSAC compounds described herein are believed to be useful inthe treatment of haematological malignancies, e.g., multiple myeloma,leukaemia, or lymphoma (e.g., non-Hodgkin Lymphoma), e.g.,haematological malignancies, multiple myeloma, leukaemia, or lymphoma(e.g., non-Hodgkin Lymphoma) associated with activation of NFκB, withaberrant NFκB signalling, or with inflammation.

Thus, the APSAC compounds described herein are believed to be useful inthe treatment of solid tumour cancers, e.g., cancer of the bladder,breast cancer (female and/or male), colon cancer, kidney cancer, lungcancer, pancreatic cancer, prostate cancer, brain cancer, skin cancer,thyroid cancer, or melanoma, e.g., solid tumour cancers, cancer of thebladder, breast cancer (female and/or male), colon cancer, kidneycancer, lung cancer, pancreatic cancer, prostate cancer, brain cancer,skin cancer, thyroid cancer, and melanoma associated with activation ofNFκB, with aberrant NFκB signalling, or with inflammation.

Thus, the APSAC compounds described herein are believed to be useful inthe treatment of a haematological malignancy, e.g., T-cell lymphoblasticlymphoma, mantle cell lymphoma, or acute lymphoblastic leukemia, e.g., ahaematological malignancy, T-cell lymphoblastic lymphoma, mantle celllymphoma, or acute lymphoblastic leukemia associated with inactivationor impairment of caspase induction or with aberrant caspase signalling,e.g., alone, or in combination with, and to augment the efficacy of,radiotherapy or chemotherapy.

Thus, the APSAC compounds described herein are believed to be useful inthe treatment of a solid tumour cancer, e.g., renal cell carcinoma,breast cancer (female and/or male), gastric cancer, prostate cancer,colon cancer or basal cell ameloblastoma, e.g., a solid tumour cancer,e.g., renal cell carcinoma, breast cancer (female and/or male), gastriccancer, prostate cancer, colon cancer, or basal cell ameloblastomaassociated with inactivation or impairment of caspase induction or withaberrant caspase signalling, e.g., alone or in combination with, and toaugment the efficacy of, radiotherapy or chemotherapy.

Use in Methods of Inhibition

One aspect of the invention pertains to a method of inhibiting aninflammatory response, in vitro or in vivo, comprising contacting animmune system component with an effective amount of an APSAC compound,as described herein.

One aspect of the invention pertains to a method of inhibiting cellularand/or molecular pathways leading to joint destruction, in vitro or invivo, comprising contacting cells associated with an immune responsewith a therapeutically-effective amount of an APSAC compound, asdescribed herein.

One aspect of the invention pertains to a method of inhibitingosteoclast survival, formation, and/or activity, in vitro or in vivo,comprising contacting an osteoclast with an effective amount of an APSACcompound, as described herein.

One aspect of the invention pertains to a method of inhibiting boneresorption, in vitro or in vivo, comprising contacting cells in the bonemicroenvironment with a therapeutically-effective amount of an APSACcompound, as described herein.

The term “immune system component,” as used herein, relates to, but isnot restricted to, cells such as macrophages, T-cells, B-cells,NK-cells, monocytes, neutrophils, dendritic cells, lymphocytes,leukocytes, granulocytes, antigen-presenting cells, and other cells ofthe haematopoietic lineage including osteoclasts.

The term “cells in the bone microenvironment,” as used herein, pertainsto cells such as osteoblasts, osteoclasts, osteocytes, and bone marrowstromal cells, which are located in close proximity to bone (e.g.,within one hundred micrometers of the bone surface).

Use in Methods of Therapy

Another aspect of the present invention pertains to an APSAC compound,as described herein, for use in a method of treatment of the human oranimal body by therapy.

Use in the Manufacture of Medicaments

Another aspect of the present invention pertains to use of an APSACcompound, as described herein, in the manufacture of a medicament foruse in treatment.

In one embodiment, the medicament comprises the APSAC compound.

Methods of Treatment

Another aspect of the present invention pertains to a method oftreatment comprising administering to a patient in need of treatment atherapeutically effective amount of an APSAC compound, as describedherein, preferably in the form of a pharmaceutical composition.

Diseases and Disorders

In one embodiment, the treatment is treatment of an inflammatorydisorder or an autoimmune disorder.

In one embodiment, the treatment is treatment of a disorder associatedwith inflammation and/or activation of the immune system.

In one embodiment, the treatment is treatment of a disorder mediated byexcessive and/or inappropriate and/or prolonged activation of the immunesystem.

In one embodiment, the treatment is treatment of inflammation.

In one embodiment, the treatment is treatment of a disorder associatedwith inflammation or activation of the immune system.

In one embodiment, the treatment is treatment of rheumatoid arthritis.

In one embodiment, the treatment is treatment of psoriasis.

In one embodiment, the treatment is treatment of psoriatic arthritis.

In one embodiment, the treatment is treatment of chronic obstructivepulmonary disease (COPD).

In one embodiment, the treatment is treatment of atherosclerosis.

In one embodiment, the treatment is treatment of ankylosing spondylitis.

In one embodiment, the treatment is treatment of inflammatory boweldisease.

In one embodiment, the treatment is prevention of an immune responseleading to organ or graft rejection following transplant.

In one embodiment, the treatment is treatment of a tumour which overexpresses TNFα, IL-1, RANKL, or NFκB, or in which inhibition of TNFα,IL-1, RANKL, or NFκB facilitates or improves the action of cytotoxictumouricidal agents.

In one embodiment, the treatment is treatment of a haematologicalmalignancy, e.g., multiple myeloma, leukaemia, or lymphoma (e.g.,non-Hodgkin Lymphoma), e.g., a haematological malignancy, multiplemyeloma, leukaemia, or lymphoma (e.g., non-Hodgkin Lymphoma) associatedwith activation of NFκB, with aberrant NFκB signalling, or withinflammation, e.g., alone, or in combination with, and to augment theefficacy of, radiotherapy or chemotherapy.

In one embodiment, the treatment is treatment of a solid tumour cancer,e.g., cancer of the bladder, breast cancer (female and/or male), coloncancer, kidney cancer, lung cancer, pancreatic cancer, prostate cancer,brain cancer, skin cancer, thyroid cancer, or melanoma, e.g., a solidtumour cancer, cancer of the bladder, breast cancer (female and/ormale), colon cancer, kidney cancer, lung cancer, pancreatic cancer,prostate cancer, brain cancer, skin cancer, thyroid cancer, and melanomaassociated with activation of NFκB, with aberrant NFκB signalling, orwith inflammation, e.g., alone, or in combination with, and to augmentthe efficacy of, radiotherapy or chemotherapy.

In one embodiment, the treatment is treatment of a haematologicalmalignancy, e.g., T-cell lymphoblastic lymphoma, mantle cell lymphoma,or acute lymphoblastic leukemia, e.g., a haematological malignancy,T-cell lymphoblastic lymphoma, mantle cell lymphoma, or acutelymphoblastic leukemia associated with inactivation or impairment ofcaspase induction or with aberrant caspase signalling, e.g., alone or incombination with, and to augment the efficacy of, radiotherapy orchemotherapy.

In one embodiment, the treatment is treatment of a solid tumour cancer,e.g., renal cell carcinoma, breast cancer (female and/or male), gastriccancer, prostate cancer, colon cancer, or basal cell ameloblastoma,e.g., a solid tumour cancer, e.g., renal cell carcinoma, breast cancer(female and/or male), gastric cancer, prostate cancer, colon cancer, orbasal cell ameloblastoma associated with inactivation or impairment ofcaspase induction or with aberrant caspase signalling, e.g., alone, orin combination with, and to augment the efficacy of, radiotherapy orchemotherapy.

In one embodiment, the treatment is part of treatment by combinationtherapy, e.g., in combination with, and to augment the efficacy of,radiotherapy or chemotherapy.

In one embodiment, the treatment is treatment of a disease or disorderselected from: diseases having an inflammatory or autoimmune component,including asthma, atherosclerosis, allergic diseases, such as atopy,allergic rhinitis, atopic dermatitis, anaphylaxis, allergicbronchopulmonary aspergillosis, and hypersensitivity pneumonitis (pigeonbreeders disease, farmer's lung disease, humidifier lung disease, maltworkers' lung disease); allergies, including flea allergy dermatitis inmammals such as domestic animals, e.g., dogs and cats, contact allergensincluding mosquito bites or other insect sting allergies, poison ivy,poison oak, poison sumac, or other skin allergens; autoimmune disorders,including, but not limited to, type I diabetes and associatedcomplications, multiple sclerosis, arthritis, systemic lupuserythematosus, autoimmune (Hasimoto's) thyroiditis, autoimmune liverdiseases such as hepatitis and primary biliary cirrhosis,hyperthyroidism (Graves' disease; thyrotoxicosis), insulin-resistantdiabetes, autoimmune adrenal insufficiency (Addison's disease),autoimmune oophoritis, autoimmune orchitis, autoimmune hemolytic anemia,paroxysmal cold hemoglobinuria, Behcet's disease, autoimmunethrombocytopenia, autoimmune neutropenia, pernicious anemia, pure redcell anemia, autoimmune coagulopathies, myasthenia gravis, experimentalallergic encephalomyelitis, autoimmune polyneuritis, pemphigus and otherbullous diseases, rheumatic carditis, Goodpasture's syndrome,postcardiotomy syndrome, Sjogren's syndrome, polymyositis,dermatomyositis, and scleroderma; disease states resulting frominappropriate inflammation, either local or systemic, for example,irritable or inflammatory bowel syndrome (Mazzucchelli et al., 1996, J.Pathol., Vol. 178, p. 201), skin diseases such as lichen planus, delayedtype hypersensitivity, chronic pulmonary inflammation, e.g., pulmonaryalveolitis and pulmonary granuloma, gingival inflammation or otherperiodontal disease, and osseous inflammation associated with lesions ofendodontic origin (Volejnikova et al., 1997, Am. J. Pathol., Vol. 150,p. 1711), hypersensitivity lung diseases such as hypersensitivitypneumonitis (Sugiyama et al., 1995, Eur. Respir. J., Vol. 8, p. 1084),and inflammation related to histamine release from basophils (Dvorak etal., 1996, J. Allergy Clin. Immunol., Vol. 98, p. 355), such as hayfever, histamine release from mast cells (Galli et al., 1989, CibaFoundation Symposium, Vol. 147, p. 53), or mast cell tumours, types oftype 1 hypersensitivity reactions (anaphylaxis, skin allergy, hives,gout, allergic rhinitis, and allergic gastroenteritis); ulcerativecolitis or Crohn's disease; TNFα induced polycystic kidney disease (Liet al., 2008, Nature Medicine, Vol. 14(8), p. 863); orCryopyrin-Associated Periodic Syndromes, including Muckle-WellsSyndrome.

In one embodiment, the treatment is treatment of a disorder mediated byosteoclasts.

In one embodiment, the treatment is treatment of a disordercharacterised by excessive bone resorption.

In one embodiment, the treatment is treatment of bone loss.

In one embodiment, the treatment is treatment of bone loss associatedwith inflammation.

In one embodiment, the treatment is treatment of bone loss notassociated with inflammation.

In one embodiment, the treatment is treatment of bone loss associatedwith excessive osteoclast activation.

In one embodiment, the treatment is treatment of joint destruction.

In one embodiment, the treatment is treatment of joint destructionassociated with inflammation.

In one embodiment, the treatment is treatment of joint destructionassociated with excessive osteoclast activation.

In one embodiment, the treatment is treatment of bone loss associatedwith rheumatoid arthritis, osteoporosis, cancer-associated bone disease,or Paget's disease of bone.

In one embodiment, the treatment is treatment of rheumatoid arthritis,osteoporosis, cancer-associated bone disease, or Paget's disease ofbone.

In one embodiment, the treatment is treatment of neoplasia of bones,whether as a primary tumour or as metastases, including but not limitedto, osteosarcoma and osteoma (Zheng et al., 1998, J. Cell Biochem., Vol.70, p. 121) and cancer-associated bone disease (e.g., hypercalcemia ofmalignancy, bone metastases, osteolytic bone metastases, multiplemyeloma, breast carcinoma).

In one embodiment, the treatment is treatment of hypercalcemia caused byconditions associated with increased bone resorption, including, but notlimited to: vitamin D intoxication, primary or tertiaryhyperparathyroidism, immobilisation, and sarcoidosis.

In one embodiment, the treatment is treatment of aseptic loosening ofprosthetic implants (e.g., artificial joints, e.g., knees, hips, etc.,can loosen due to osteoclast activity driven by local inflammation)(see, e.g., Childs, L. M., et al., 2001, Journal of Bone and MineralResearch, Vol. 16, No. 2, pp. 338-347).

In one embodiment, the treatment is treatment of osteopetrosis,osteoarthritis, or ectopic bone formation.

Treatment

The term “treatment,” as used herein in the context of treating acondition, pertains generally to treatment and therapy, whether of ahuman or an animal (e.g., in veterinary applications), in which somedesired therapeutic effect is achieved, for example, the inhibition ofthe progress of the condition, and includes a reduction in the rate ofprogress, a halt in the rate of progress, alleviatiation of symptoms ofthe condition, amelioration of the condition, and cure of the condition.Treatment as a prophylactic measure (i.e., prophylaxis) is alsoincluded. For example, use with patients who have not yet developed thecondition, but who are at risk of developing the condition, isencompassed by the term “treatment.”

For example, use with perimenopausal women who may not yet haveosteoporosis, but who are at risk of osteoporosis, is encompassed by theterm “treatment.”

The term “therapeutically-effective amount,” as used herein, pertains tothat amount of a compound, or a material, composition or dosage formcomprising a compound, which is effective for producing some desiredtherapeutic effect, commensurate with a reasonable benefit/risk ratio,when administered in accordance with a desired treatment regimen.

The term “treatment” includes combination treatments and therapies, inwhich two or more treatments or therapies are combined, for example,sequentially or simultaneously. Examples of treatments and therapiesinclude, but are not limited to, chemotherapy (the administration ofactive agents, including, e.g., drugs, antibodies (e.g., as inimmunotherapy), prodrugs (e.g., as in photodynamic therapy, GDEPT,ADEPT, etc.); surgery; radiation therapy; and gene therapy.

Other Uses

The APSAC compounds described herein may also be used as cell cultureadditives to inhibit immune cell function, for example, to inhibit thesurvival, formation, and/or activity of macrophages, T-cells, or othercells involved in the immune response.

The APSAC compounds, as described herein, may also be used as cellculture additives, for example, to inhibit osteoclasts, for example, toinhibit the survival, formation, and/or activity of osteoclasts.

The APSAC compounds described herein may also be used as part of an invitro assay, for example, in order to determine whether a candidate hostis likely to benefit from treatment with the compound in question.

The APSAC compounds described herein may also be used as a standard, forexample, in an assay, in order to identify other active compounds, otherosteoclast inhibitors, etc.

Kits

One aspect of the invention pertains to a kit comprising (a) an APSACcompound as described herein, or a composition comprising an APSACcompound as described herein, e.g., preferably provided in a suitablecontainer and/or with suitable packaging; and (b) instructions for use,e.g., written instructions on how to administer the compound orcomposition.

The written instructions may also include a list of indications forwhich the APSAC compound is a suitable treatment.

Routes of Administration

The APSAC compound or pharmaceutical composition comprising the APSACcompound may be administered to a subject by any convenient route ofadministration, whether systemically/peripherally or topically (i.e., atthe site of desired action).

Routes of administration include, but are not limited to, oral (e.g., byingestion); buccal; sublingual; transdermal (including, e.g., by apatch, plaster, etc.); transmucosal (including, e.g., by a patch,plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., byeyedrops); pulmonary (e.g., by inhalation or insufflation therapy using,e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., bysuppository or enema); vaginal (e.g., by pessary); parenteral, forexample, by injection, including subcutaneous, intradermal,intramuscular, intravenous, intraarterial, intracardiac, intrathecal,intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal,intratracheal, subcuticular, intraarticular, subarachnoid, andintrasternal; by implant of a depot or reservoir, for example,subcutaneously or intramuscularly.

The Subject/Patient

The subject/patient may be a chordate, a vertebrate, a mammal, aplacental mammal, a marsupial (e.g., kangaroo, wombat), a rodent (e.g.,a guinea pig, a hamster, a rat, a mouse), murine (e.g., a mouse), alagomorph (e.g., a rabbit), avian (e.g., a bird), canine (e.g., a dog),feline (e.g., a cat), equine (e.g., a horse), porcine (e.g., a pig),ovine (e.g., a sheep), bovine (e.g., a cow), a primate, simian (e.g., amonkey or ape), a monkey (e.g., marmoset, baboon), an ape (e.g.,gorilla, chimpanzee, orangutan, gibbon), or a human.

Furthermore, the subject/patient may be any of its forms of development,for example, a fetus.

In one preferred embodiment, the subject/patient is a human.

Formulations

While it is possible for the APSAC compound to be administered alone, itis preferable to present it as a pharmaceutical formulation (e.g.,composition, preparation, medicament) comprising at least one APSACcompound, as described herein, together with one or more otherpharmaceutically acceptable ingredients well known to those skilled inthe art, including, but not limited to, pharmaceutically acceptablecarriers, diluents, excipients, adjuvants, fillers, buffers,preservatives, anti-oxidants, lubricants, stabilisers, solubilisers,surfactants (e.g., wetting agents), masking agents, colouring agents,flavouring agents, and sweetening agents. The formulation may furthercomprise other active agents, for example, other therapeutic orprophylactic agents.

Thus, the present invention further provides pharmaceuticalcompositions, as defined above, and methods of making a pharmaceuticalcomposition comprising admixing at least one APSAC compound, asdescribed herein, together with one or more other pharmaceuticallyacceptable ingredients well known to those skilled in the art, e.g.,carriers, diluents, excipients, etc. If formulated as discrete units(e.g., tablets, etc.), each unit contains a predetermined amount(dosage) of the compound.

The term “pharmaceutically acceptable,” as used herein, pertains tocompounds, ingredients, materials, compositions, dosage forms, etc.,which are, within the scope of sound medical judgment, suitable for usein contact with the tissues of the subject in question (e.g., human)without excessive toxicity, irritation, allergic response, or otherproblem or complication, commensurate with a reasonable benefit/riskratio. Each carrier, diluent, excipient, etc. must also be “acceptable”in the sense of being compatible with the other ingredients of theformulation.

Suitable carriers, diluents, excipients, etc. can be found in standardpharmaceutical texts, for example, Remington's Pharmaceutical Sciences,18th edition, Mack Publishing Company, Easton, Pa., 1990; and Handbookof Pharmaceutical Excipients, 5th edition, 2005.

The formulations may be prepared by any methods well known in the art ofpharmacy. Such methods include the step of bringing into association thecompound with a carrier which constitutes one or more accessoryingredients. In general, the formulations are prepared by uniformly andintimately bringing into association the compound with carriers (e.g.,liquid carriers, finely divided solid carrier, etc.), and then shapingthe product, if necessary.

The formulation may be prepared to provide for rapid or slow release;immediate, delayed, timed, or sustained release; or a combinationthereof.

Formulations may suitably be in the form of liquids, solutions (e.g.,aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous),emulsions (e.g., oil-in-water, water-in-oil), elixirs, syrups,electuaries, mouthwashes, drops, tablets (including, e.g., coatedtablets), granules, powders, losenges, pastilles, capsules (including,e.g., hard and soft gelatin capsules), cachets, pills, ampoules,boluses, suppositories, pessaries, tinctures, gels, pastes, ointments,creams, lotions, oils, foams, sprays, mists, or aerosols.

Formulations may suitably be provided as a patch, adhesive plaster,bandage, dressing, or the like which is impregnated with one or morecompounds and optionally one or more other pharmaceutically acceptableingredients, including, for example, penetration, permeation, andabsorption enhancers. Formulations may also suitably be provided in theform of a depot or reservoir.

The compound may be dissolved in, suspended in, or admixed with one ormore other pharmaceutically acceptable ingredients. The compound may bepresented in a liposome or other microparticulate which is designed totarget the compound, for example, to blood components or one or moreorgans.

Formulations suitable for oral administration (e.g., by ingestion)include liquids, solutions (e.g., aqueous, non-aqueous), suspensions(e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water,water-in-oil), elixirs, syrups, electuaries, tablets, granules, powders,capsules, cachets, pills, ampoules, boluses.

Formulations suitable for buccal administration include mouthwashes,losenges, pastilles, as well as patches, adhesive plasters, depots, andreservoirs. Losenges typically comprise the compound in a flavoredbasis, usually sucrose and acacia or tragacanth. Pastilles typicallycomprise the compound in an inert matrix, such as gelatin and glycerin,or sucrose and acacia. Mouthwashes typically comprise the compound in asuitable liquid carrier.

Formulations suitable for sublingual administration include tablets,losenges, pastilles, capsules, and pills.

Formulations suitable for oral transmucosal administration includeliquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g.,aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil),mouthwashes, losenges, pastilles, as well as patches, adhesive plasters,depots, and reservoirs.

Formulations suitable for non-oral transmucosal administration includeliquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g.,aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil),suppositories, pessaries, gels, pastes, ointments, creams, lotions,oils, as well as patches, adhesive plasters, depots, and reservoirs.

Formulations suitable for transdermal administration include gels,pastes, ointments, creams, lotions, and oils, as well as patches,adhesive plasters, bandages, dressings, depots, and reservoirs.

Tablets may be made by conventional means, e.g., compression ormoulding, optionally with one or more accessory ingredients. Compressedtablets may be prepared by compressing in a suitable machine thecompound in a free-flowing form such as a powder or granules, optionallymixed with one or more binders (e.g., povidone, gelatin, acacia,sorbitol, tragacanth, hydroxypropylmethyl cellulose); fillers ordiluents (e.g., lactose, microcrystalline cellulose, calcium hydrogenphosphate); lubricants (e.g., magnesium stearate, talc, silica);disintegrants (e.g., sodium starch glycolate, cross-linked povidone,cross-linked sodium carboxymethyl cellulose); surface-active ordispersing or wetting agents (e.g., sodium lauryl sulfate);preservatives (e.g., methyl p-hydroxybenzoate, propyl p-hydroxybenzoate,sorbic acid); flavours, flavour enhancing agents, and sweeteners.Moulded tablets may be made by moulding in a suitable machine a mixtureof the powdered compound moistened with an inert liquid diluent. Thetablets may optionally be coated or scored and may be formulated so asto provide slow or controlled release of the compound therein using, forexample, hydroxypropylmethyl cellulose in varying proportions to providethe desired release profile. Tablets may optionally be provided with acoating, for example, to affect release, for example an enteric coating,to provide release in parts of the gut other than the stomach.

Ointments are typically prepared from the compound and a paraffinic or awater-miscible ointment base.

Creams are typically prepared from the compound and an oil-in-watercream base. If desired, the aqueous phase of the cream base may include,for example, at least about 30% w/w of a polyhydric alcohol, i.e., analcohol having two or more hydroxyl groups such as propylene glycol,butane-1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycoland mixtures thereof. The topical formulations may desirably include acompound which enhances absorption or penetration of the compoundthrough the skin or other affected areas. Examples of such dermalpenetration enhancers include dimethylsulfoxide and related analogues.

Emulsions are typically prepared from the compound and an oily phase,which may optionally comprise merely an emulsifier (otherwise known asan emulgent), or it may comprises a mixture of at least one emulsifierwith a fat or an oil or with both a fat and an oil. Preferably, ahydrophilic emulsifier is included together with a lipophilic emulsifierwhich acts as a stabiliser. It is also preferred to include both an oiland a fat. Together, the emulsifier(s) with or without stabiliser(s)make up the so-called emulsifying wax, and the wax together with the oiland/or fat make up the so-called emulsifying ointment base which formsthe oily dispersed phase of the cream formulations.

Suitable emulgents and emulsion stabilisers include Tween 60, Span 80,cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodiumlauryl sulfate. The choice of suitable oils or fats for the formulationis based on achieving the desired cosmetic properties, since thesolubility of the compound in most oils likely to be used inpharmaceutical emulsion formulations may be very low. Thus the creamshould preferably be a non-greasy, non-staining and washable productwith suitable consistency to avoid leakage from tubes or othercontainers. Straight or branched chain, mono- or dibasic alkyl esterssuch as di-isoadipate, isocetyl stearate, propylene glycol diester ofcoconut fatty acids, isopropyl myristate, decyl oleate, isopropylpalmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branchedchain esters known as Crodamol CAP may be used, the last three beingpreferred esters. These may be used alone or in combination depending onthe properties required. Alternatively, high melting point lipids suchas white soft paraffin and/or liquid paraffin or other mineral oils canbe used.

Formulations suitable for intranasal administration, where the carrieris a liquid, include, for example, nasal spray, nasal drops, or byaerosol administration by nebuliser, include aqueous or oily solutionsof the compound.

Formulations suitable for intranasal administration, where the carrieris a solid, include, for example, those presented as a coarse powderhaving a particle size, for example, in the range of about 20 to about500 microns which is administered in the manner in which snuff is taken,i.e., by rapid inhalation through the nasal passage from a container ofthe powder held close up to the nose.

Formulations suitable for pulmonary administration (e.g., by inhalationor insufflation therapy) include those presented as an aerosol sprayfrom a pressurised pack, with the use of a suitable propellant, such asdichlorodifluoromethane, trichlorofluoromethane,dichoro-tetrafluoroethane, carbon dioxide, or other suitable gases.

Formulations suitable for ocular administration include eye dropswherein the compound is dissolved or suspended in a suitable carrier,especially an aqueous solvent for the compound.

Formulations suitable for rectal administration may be presented as asuppository with a suitable base comprising, for example, natural orhardened oils, waxes, fats, semi-liquid or liquid polyols, for example,cocoa butter or a salicylate; or as a solution or suspension fortreatment by enema.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining in addition to the compound, such carriers as are known inthe art to be appropriate.

Formulations suitable for parenteral administration (e.g., byinjection), include aqueous or non-aqueous, isotonic, pyrogen-free,sterile liquids (e.g., solutions, suspensions), in which the compound isdissolved, suspended, or otherwise provided (e.g., in a liposome orother microparticulate). Such liquids may additional contain otherpharmaceutically acceptable ingredients, such as anti-oxidants, buffers,preservatives, stabilisers, bacteriostats, suspending agents, thickeningagents, and solutes which render the formulation isotonic with the blood(or other relevant bodily fluid) of the intended recipient. Examples ofexcipients include, for example, water, alcohols, polyols, glycerol,vegetable oils, and the like. Examples of suitable isotonic carriers foruse in such formulations include Sodium Chloride Injection, Ringer'sSolution, or Lactated Ringer's Injection. Typically, the concentrationof the compound in the liquid is from about 1 ng/mL to about 100 μg/mL,for example from about 10 ng/mL to about 10 μg/mL, for example fromabout 10 ng/mL to about 1 μg/mL. The formulations may be presented inunit-dose or multi-dose sealed containers, for example, ampoules andvials, and may be stored in a freeze-dried (lyophilised) conditionrequiring only the addition of the sterile liquid carrier, for examplewater for injections, immediately prior to use. Extemporaneous injectionsolutions and suspensions may be prepared from sterile powders,granules, and tablets.

Dosage

It will be appreciated by one of skill in the art that appropriatedosages of the APSAC compounds, and compositions comprising the APSACcompounds, can vary from patient to patient. Determining the optimaldosage will generally involve the balancing of the level of therapeuticbenefit against any risk or deleterious side effects. The selecteddosage level will depend on a variety of factors including, but notlimited to, the activity of the particular APSAC compound, the route ofadministration, the time of administration, the rate of excretion of theAPSAC compound, the duration of the treatment, other drugs, compounds,and/or materials used in combination, the severity of the condition, andthe species, sex, age, weight, condition, general health, and priormedical history of the patient. The amount of APSAC compound and routeof administration will ultimately be at the discretion of the physician,veterinarian, or clinician, although generally the dosage will beselected to achieve local concentrations at the site of action whichachieve the desired effect without causing substantial harmful ordeleterious side-effects.

Administration can be effected in one dose, continuously orintermittently (e.g., in divided doses at appropriate intervals)throughout the course of treatment. Methods of determining the mosteffective means and dosage of administration are well known to those ofskill in the art and will vary with the formulation used for therapy,the purpose of the therapy, the target cell(s) being treated, and thesubject being treated. Single or multiple administrations can be carriedout with the dose level and pattern being selected by the treatingphysician, veterinarian, or clinician.

In general, a suitable dose of the APSAC compound is in the range ofabout 10 μg to about 250 mg (more typically about 100 μg to about 25 mg)per kilogram body weight of the subject per day. Where the compound is asalt, an ester, an amide, a prodrug, or the like, the amountadministered is calculated on the basis of the parent compound and sothe actual weight to be used is increased proportionately.

EXAMPLES

The following examples are provided solely to illustrate the presentinvention and are not intended to limit the scope of the invention, asdescribed herein.

Chemical Synthesis

Synthesis 1 4-Bromo-N-(trans-4-hydroxycyclohexyl)benzenesulfonamide(ABD598)

Method A: 4-Bromobenzene sulfonyl chloride (1 g) was dissolved in DCM(30 mL). Trans-4-aminocyclohexanol hydrochloride (1 g) was added,followed by pyridine (3 mL). The mixture was stirred for 3 hours, givinga brick red suspension, and then poured into 2 M HCl and separated. Theorganic phase was collected and the aqueous phase washed with ethylacetate. The two organic phases were combined and the resultant solutionwas dried and evaporated to give an orange residue. The residue wasrecrystallised from ethyl acetate/petrol, filtered and the resultantpowder boiled with ether and the title compound obtained as a whitepowder. ¹³C NMR (62.5 MHz, DMSO-d₆): δ 31.0, 33.6, 51.8, 67.6, 125.9,128.3, 132.1 and 141.5.

Synthesis 22′,4′-Difluoro-N-(trans-4-hydroxycyclohexyl)biphenyl-4-sulfonamide(ABD599)

Method B: ABD598 (1.0 g) was dissolved in a mixture of toluene (15 mL)and ethanol (15 mL). 2,4-Difluorophenylboronic acid (1 g) was addedfollowed by (PPh₃)₄Pd (0.15 g). The mixture was stirred vigorously underN₂ and 2 M Na₂CO₃ (15 mL) added. The mixture was refluxed with stirringfor 3 hours under an atmosphere of N₂. The organic solvents were removedunder vacuum, the residue dissolved in ethyl acetate and washed withwater and saturated NaCl solution. After drying (Na₂SO₄), the solventwas evaporated and the brown residue was purified by columnchromatography (ethyl acetate/petrol) and the title compound wasobtained as a white powder (0.4 g). ¹H NMR (250 MHz, DMSO-d₆): δ 1.15(4H, m), 1.70 (4H, m), 2.92 (1H, m), 3.28 (1H, m), 4.51 (1H, d, J=4.3Hz), 7.23 (1H, t, J=8.5 Hz), 7.42 (1H, t, J=9.2 Hz), 7.66 (2H, m), 7.74(2H, d, J=8.2 Hz) and 7.90 (2H, d, J=8.2 Hz). MS, m/z: Calcd, 367.11;Found, 367.32 (M).

Synthesis 34′-Chloro,2′-fluoro-N-(trans-4-hydroxycyclohexyl)biphenyl-4-sulfonamide(ABD655)

Using a method analogous to Method B, with ABD598 and 4-chloro,2-fluorophenylboronic acid, the title compound was obtained as a whitepowder. ¹H NMR (250 MHz, DMSO-d₆): δ 1.11 (4H, m), 1.66 (4H, m), 2.94(1H, s), 3.30 (1H, s), 4.49 (1H, d, J=4.3 Hz), 7.43 (1H, d, J=8.2 Hz),7.58 (1H, s), 7.63 (1H, d, J=7.3 Hz), 7.68 (1H, m), 7.76 (2H, d, J=7.6Hz) and 7.91 (2H, d, J=8.2 Hz). ¹³C NMR (62.5 MHz, DMSO-d₆): δ 31.1,33.6, 51.8, 67.6, 116.7, 125.3, 125.9 (d, J=13.7 Hz), 126.5, 129.7,132.0, 133.9, 137.6, 141.8, 159.0 (d, J=251.0 Hz). MS, m/z: Calcd,383.076; Found, 383.25 (M).

Synthesis 4 2′,4′-Difluorobiphenylsulfonyl chloride

2,4-Difluorophenylboronic acid (15 g, 129 mmol) was added to a solutionof bromobenzene (19.8 g, 126 mmol) in DME (500 mL). To this was added asolution of sodium carbonate (55.8 g, 520 mmol) in water (260 mL). Thesolution was degassed by bubbling argon through the mixture and thenstirred under argon. Pd(dppf)Cl₂ (1.5 g, 2.1 mmol) was added and themixture heated overnight at 90° C. under argon. The mixture was cooledto room temperature and water (150 mL) and ethyl acetate (500 mL) wereadded. The layers were separated and the organic layer was washed with 2M NaOH (100 mL), water (100 mL) and brine (100 mL). The black ethylacetate layer was dried over MgSO₄, charcoal was added, and the mixturewas filtered through a short pad of silica. Evaporation of the solventsgave 2,4-difluorobiphenyl as a brown oil, which crystallised on standing(21.2 g).

2,4-Difluorobiphenyl (21.2 g, 111 mmol) was dissolved in chloroform (120mL) and chlorosulfonic acid (12.5 mL, 188 mmol) was added dropwise. Themixture was stirred overnight at room temperature. The reaction mixturewas concentrated in vacuo and the residue taken up into EtOAc (100 mL)and washed with water (3×25 mL). The organics were shaken with brine,whereupon a flocculent solid formed. This was filtered and washed withEtOAc and dried to give 2′,4′-difluorobiphenyl-4-sulfonic acid as anoff-white solid (12.1 g).

2′,4′-Difluorobiphenyl-4-sulphonic acid (12.1 g, 47 mmol) was suspendedin thionyl chloride (100 mL). The mixture was heated at reflux for 30minutes, when a catalytic amount of dry DMF was added and the reactionmixture was heated at reflux for a further 4 hours. The reaction mixturewas then cooled, the thionyl chloride evaporated and the residue wasthen azeotroped with toluene (3×10 mL). The resulting yellow/orange gumwas taken up into EtOAc (250 mL) and washed with water (50 mL) and brine(50 mL), and dried over MgSO₄. Filtration and evaporation gave the titlecompound as a brown oil which crystallized on standing (11 g).

Synthesis 5 (1R,3S)-Methyl 3-aminocyclopentanecarboxylate hydrochloride

A suspension of (1R,3S)-3-aminocyclopentanecarboxylic acid (500 mg, 3.8mmol) in methanol (10 mL) was stirred at 0° C. and thionyl chloride(1.40 mL, 19.3 mmol) was added dropwise. The mixture was allowed to warmto room temperature and stirred overnight. The resulting clear solutionwas evaporated, azeotroped with methanol (2×5 mL), air-dried and thetitle compound obtained as a white powder (680 mg).

Synthesis 6 (1R,3S)-Methyl3-(2′,4′-difluorobiphenyl-4-ylsulfonamido)cyclopentanecarboxylate(ABD773a)

Using a method analogous to Method A, using (1R,3S)-methyl3-aminocyclopentanecarboxylate and 2′,4′-difluorobiphenyl-4-sulphonylchloride, the title compound was obtained as a pale yellow gum.

Synthesis 72′,4′-Difluoro-N-((1S,3R)-3-(hydroxymethyl)cyclopentyl)biphenyl-4-sulfonamide(ABD773)

A solution of 1 M LiAlH₄ in THF (1.85 mL, 1.85 mmol) was added dropwiseto a stirred solution of ABD773a (148 mg, 0.37 mmol) in THF (5 mL) at 0°C., then stirred at room temperature overnight. The mixture waspartitioned between water (10 mL) and EtOAc (20 mL), separated and theaqueous layer extracted with further EtOAc (10 mL). The organic phasewas washed with brine (10 mL) and dried over MgSO₄. The solvent wasevaporated, the residue purified by flash chromatography (SiO₂, 20%acetone/hexane) and the title compound obtained as a light brown gum(133 mg). ¹H NMR (300 MHz, CDCl₃): δ 1.24-1.27 (2H, m), 1.50-1.58 (2H,m), 1.66-1.76 (2H, m), 1.96-2.08 (1H, m), 2.12-2.22 (1H, m), 3.59 (2H,m), 3.70-3.78 (1H, m), 5.25-5.30 (1H, m), 6.90-7.10 (2H, m), 7.42-7.48(1H, m), 7.63 (2H, d, J=8 Hz) and 7.93 (2H, d, J=8 Hz). MS, m/z: Calcd,367.11; Found, 368.07 (M+H).

Synthesis 8 Methyl trans-4-aminocyclohexanecarboxylate

A suspension of trans-4-amino-cyclohexanecarboxylic acid (5.0 g, 34.9mmol) in methanol (50 mL) was stirred at room temperature and SOCl₂(7.14 mL, 11.7 g, 98.4 mmol) was added dropwise over 20 minutes. Thesolid dissolved, giving a brown solution, which was stirred overnight.The solvent was removed under reduced pressure, giving a brown solid,which was triturated with ether, redissolved in methanol (20 mL) andagain evaporated to give a slightly sticky brown solid (6.52 g). Aportion of the product (820 mg) was dissolved in methanol (10 mL) andsplit in two batches, each of which was loaded onto a 5 g SCX column.These were eluted with MeOH (2×10 mL) and then 2 M NH₃/MeOH (4×10 mL),and the title compound obtained as a beige solid (425 mg combined).

Synthesis 9 Methyl4-(2′,4′-difluorobiphenyl-4-ylsulfonamido)trans-cyclohexanecarboxylate(ABD776a)

Using a method analogous to Method A with2′,4′-difluorobiphenyl-4-sulfonyl chloride and methyltrans-4-aminocyclohexanecarboxylate, the title compound was obtained asa white solid.

Synthesis 102′,4′-Difluoro-N-(4-(trans-hydroxymethyl)cyclohexyl)biphenyl-4-sulfonamide(ABD776)

A solution of ABD776a (100 mg, 0.24 mmol) in dry THF (10 mL) was cooledto 0° C. under argon and 1 M LiAlH₄ in THF (1.22 mL, 1.22 mmol) wasadded by syringe. The mixture was stirred overnight, allowing it to warmto room temperature. The solution was then cooled to 0° C. beforesaturated NH₄Cl (5 mL) and EtOAc (20 mL) were added. The mixture wasfiltered through Celite and the layers separated. The aqueous phase wasextracted with further EtOAc (3×5 mL) and the combined organics werewashed with 1 M HCl (10 mL), water (10 mL) and brine (10 mL) and driedover MgSO₄. Evaporation of the solvents afforded a brown gum, which waspurified by SP4 chromatography (10 g Isolute II SiO₂ cartridge, 10-30%acetone/hexane) to give a light brown gum. Final purification by reversephase HPLC (40-48.5% NH₄OH/H₂O in CH₃CN) gave the title compound as awhite solid (28 mg). ¹H NMR (400 MHz, CDCl₃): δ 0.99 (2H, q, J=9 Hz),1.18 (2H, q, J=9 Hz), 1.34-1.45 (1H, m), 1.78 (2H, d, J=12 Hz), 1.93(2H, d, J=12 Hz), 3.07-3.19 (1H, m), 3.42 (2H, t, J=5 Hz), 4.32 (1H, d,J=8 Hz), 6.88-7.02 (2H, m), 7.38-7.46 (1H, m), 7.65 (2H, d, J=8 Hz) and7.94 (2H, d, J=8 Hz). MS, m/z: Calcd, 381.121; Found, 381.59 (M).

Synthesis 11 4-Bromo-N-(4-oxocyclohexyl)benzenesulfonamide (ABD777b)

Jones' reagent was prepared by dissolving CrO₃ (1.33 g, 13.3 mmol) inconcentrated H₂SO₄ (1.15 mL) and diluting the mixture up to 5 mL withwater. A solution of ABD598 (390 mg, 1.17 mmol) in acetone (15 mL) wasstirred at room temperature and Jones' reagent was added dropwise untilan orange colour persisted. TLC indicated complete consumption of thestarting material and the formation of a new, less polar, compound. Themixture was filtered through Celite, the solvent was evaporated and theresidue taken up in EtOAc (50 mL). The solution was washed with water(2×10 mL) and 10% aqueous Na₂S₂O₃ (2×10 mL) and dried over MgSO₄.Evaporation of the solvent gave the title compound as a white solid (390mg).

Synthesis 12 4-Bromo-N-(cis-4-hydroxycyclohexyl)benzenesulfonamide(ABD777a)

A solution of ABD777b (205 mg, 0.62 mmol) in dry THF (5 mL) was cooledto 0° C. under argon. 1 M LS-Selectride in THF (1.32 mL, 1.32 mmol) wasadded by syringe and the solution was stirred for 1 hour. Water (1 mL)was added and the mixture was stirred for 10 minutes before beingdiluted with EtOAc (20 mL) and 1 M HCl (4 mL). The layers were separatedand the organic phase was washed with water (5 mL) and brine (5 mL) anddried over MgSO₄. Evaporation of the solvents afforded a colourless oilwhich was purified by SP4 chromatography (20 g Isolute II SiO₂cartridge, eluting with 0-40% acetone/hexane) and the title compoundobtained as a white solid (165 mg).

Synthesis 132′,4′-Difluoro-N-(cis-4-hydroxycyclohexyl)biphenyl-4-sulfonamide(ABD777)

Method C: ABD777a (160 mg, 0.48 mmol), 2,4-difluorophenylboronic acid(113 mg, 0.72 mmol) and 1 M Na₂CO₃ solution (1 mL, 1 mmol) were stirredin DME and the flask was flushed with argon. Pd(dppf)Cl₂ (17 mg, 0.02mmol) was added and the flask was placed into an oil bath that had beenpre-heated to 90° C. and stirred for 1.5 hours. The mixture was cooled,poured into EtOAc (30 mL) and washed with water (5 mL) and brine (5 mL).The solvents were dried over MgSO₄ and evaporated to afford a dark oil,which was purified by SP4 chromatography twice (20 g Isolute II SiO₂column, eluting with 0-40% acetone/hexane, then 10 g Isolute II SiO₂column, eluting with 0-40% acetone/hexane) to give a colourless glassysolid. This was triturated with ether/hexane and the title compound wasobtained as a white powder. ¹H NMR (300 MHz, DMSO-d₆): δ 1.24-1.40 (4H,m), 1.40-1.59 (4H, m), 2.98 (1H, br s), 3.55 (1H, br s), 4.32 (1H, d,J=3 Hz), 7.21 (1H, td, J=17, 2 Hz), 7.40 (1H, td, J=20, 3 Hz), 7.60-7.80(3H, m) and 7.88 (2H, d, J=8 Hz). MS, m/z: Calcd, 367.105; Found, 367.31(M).

Synthesis 14 Methyl cis-4-aminocyclohexanecarboxylate

A suspension of cis-4-aminocyclohexanecarboxylic acid (5.0 g, 34.9 mmol)in methanol (50 mL) was stirred at room temperature and SOCl₂ (7.1 mL,98.4 mmol) was added dropwise over 20 minutes, causing the solid todissolve. The solution was stirred overnight and the methanol was thenremoved under reduced pressure. The residual solid was triturated withdiethyl ether and air-dried and the title compound obtained as anoff-white powder (6.0 g).

Synthesis 15 Methyl4-(4-bromophenylsulfonamido)cis-cyclohexanecarboxylate (ABD781b)

Using a method analogous to Method A with 4-bromophenylsulfonyl chlorideand methyl cis-4-aminocyclohexanecarboxylate, the title compound wasobtained as a pale brown solid.

Synthesis 16 Methyl4-(2′,4′-difluorobiphenyl-4-ylsulfonamido)cis-cyclohexanecarboxylate(ABD781a)

Using a method analogous to Method A with 2′,4′-difluorophenylsulfonylchloride and ABD781b, the title compound was obtained as an orange gum.

Synthesis 172′,4′-Difluoro-N-(cis-4-(hydroxymethyl)cyclohexyl)biphenyl-4-sulfonamide(ABD781)

A solution of ABD781a (123 mg, 0.30 mmol) in dry THF (3 mL) was cooledunder argon to 0° C. and 1 M LiAlH₄ in THF (1.5 mL, 1.5 mmol) was addedby syringe. The mixture was stirred for 2 hours, whilst warming to roomtemperature. Ice and water were then added and the mixture was adjustedto pH 2 with 2 M HCl and extracted with EtOAc (4×10 mL). The combinedextracts were washed with brine (10 mL), dried over MgSO₄ andevaporated. The crude product was purified by column chromatography(SiO₂, 30%-40% acetone/hexane) and then trituration with ether/hexanegave the title compound as a white solid (64 mg). ¹H NMR (300 MHz,CDCl₃): δ 1.15-1.30 (2H, m), 1.50-1.70 (7H, m), 3.45-3.56 (3H, m), 4.63(1H, d, J=7 Hz), 6.91-7.04 (2H, m), 7.43 (1H, td, J=9 Hz, 7 Hz), 7.65(2H, d, J=8 Hz) and 7.93 (2H, d, J=8 Hz). MS, m/z: Calcd, 381.12; Found,381.25 (M).

Synthesis 18 2′,4′-Difluoro-N-(4-oxocyclohexyl)biphenyl-4-sulfonamide(ABD786)

Using a method analogous to Method C, with ABD777b and2,4-difluorophenylboronic acid, the title compound was obtained as awhite powder. ¹H NMR (300 MHz, DMSO-d₆): δ 1.63 (2H, m), 1.85 (2H, m),2.25 (4H, m), 3.51 (1H, br m), 7.22 (1H, td, J=9 Hz, 3 Hz), 7.41 (1H,ddd, J=12 Hz, 8 Hz, 3 Hz), 7.65 (1H, td, J=8 Hz, 7 Hz), 7.74 (2H, dd,J=8 Hz, 2 Hz), 7.92 (2H, d, J=8 Hz) and 7.97 (1H, br s). MS, m/z: Calcd,365.09; Found, 365.52 (M).

Synthesis 192′,4′-Difluoro-N-(trans-4-(2-hydroxypropan-2-yl)cyclohexyl)biphenyl-4-sulfonamide(ABD794)

A solution of ABD776a (100 mg, 0.24 mmol) in dry THF (10 mL) was cooledunder argon to 0° C. 3 M Methylmagnesium bromide solution in Et₂O (25μL, 0.75 mmol) was added by syringe and the mixture was stirred for 2hours, allowing it to warm to room temperature. The solution was cooledto 0° C. and saturated NH₄Cl solution (2 mL) was added, followed bywater to dissolve the solids. The mixture was extracted with EtOAc (3×10mL) and the combined extracts were washed with brine (5 mL) and water (5mL) and dried over MgSO₄. The solvents were evaporated to afford a browngum, which was purified by SP4 chromatography (10 g Isolute II SiO₂cartridge, 10-40% acetone/hexane) to give a glassy solid (64 mg). Thetitle compound was obtained as a white solid by reverse phase HPLC(50-55% NH₄OH/CH₃CN) (31 mg). ¹H NMR (400 MHz, CDCl₃): δ 1.13 (6H, s),1.00-1.30 (4H, m), 1.81 (2H, d, J=12 Hz), 1.95 (2H, d, J=12 Hz),3.05-3.16 (1H, m), 4.29 (1H, d, J=7 Hz), 6.89-7.02 (2H, m), 7.43 (1H,m), 7.63 (2H, d, J=8 Hz) and 7.93 (2H, d, J=8 Hz). MS, m/z: Calcd,409.152; Found, 409.59 (M).

Synthesis 202′,4′-Difluoro-N-(cis-4-(2-hydroxypropan-2-yl)cyclohexyl)biphenyl-4-sulfonamide(ABD795)

A solution of ABD781a (300 mg, 0.73 mmol) in dry THF (10 mL) was cooledunder argon to 0° C. and 3 M methylmagnesium bromide in Et₂O (0.97 mL,2.93 mmol) was added by syringe. The ice bath was removed and thereaction mixture was stirred at room temperature for 1 hour. SaturatedNH₄Cl (2 mL) was then added and the mixture was stirred a further 10minutes before being diluted with water (10 mL) and diethyl ether (20mL). The layers were separated and the aqueous phase was extracted withdiethyl ether (2×10 mL). The combined organics were dried over MgSO₄ andevaporated to give an off-white foamy solid. This was triturated withdiethyl ether/hexane (1:1, 3×5 mL) and the title compound obtained as awhite powder (250 mg). ¹H NMR (300 MHz, DMSO-d₆): δ 0.96 (6H, s), 1.06(1H, t, J=6 Hz), 1.16-1.34 (4H, m), 1.39-1.47 (2H, m), 1.53-1.60 (2H,m), 3.22 (1H, br s), 7.22 (1H, t, J=7 Hz), 7.39 (1H, t, J=9 Hz),7.60-7.70 (1H, m), 7.72 (2H, d, J=8 Hz) and 7.88 (2H, d, J=8 Hz). MS,m/z: Calcd, 409.152; Found, 409.59 (M).

Synthesis 21 (1R,3S)-Methyl3-(4-bromophenylsulfonamido)cyclopentanecarboxylate (ABD796b)

Using a method analogous to Method A, with (1R,3S)-methyl3-aminocyclopentanecarboxylate and 4-bromobenzenesulphonyl chloride, thetitle compound was obtained as a light brown gum.

Synthesis 224-Bromo-N-((1S,3R)-3-(2-hydroxypropan-2-yl)cyclopentyl)benzenesulfonamide(ABD796a)

3 M Methylmagnesium bromide in ether (360 μL, 1.08 mmol) was added to astirred solution of ABD796b (130 mg, 0.36 mmol) in dry THF (10 mL) at 0°C. The reaction mixture was allowed to warm to room temperature andstirred overnight. Saturated ammonium chloride solution (3 mL) was addedand the THF layer was separated. The aqueous phase was extracted withTHF (2×10 mL) and the combined organic layers were washed with brine anddried over MgSO₄. Evaporation of the solvent gave the title compound asa brown gum.

Synthesis 232′,4′-Difluoro-N-((1S,3R)-3-(2-hydroxypropan-2-yl)cyclopentyl)biphenyl-4-sulfonamide(ABD796)

Using a method analogous to Method C with ABD796a and2,4-difluorophenylboronic acid, the title compound was obtained as awhite solid. ¹H NMR (300 MHz, CDCl₃): δ 1.15 (3H, s), 1.18 (3H, s),1.40-1.45 (2H, m), 1.50-1.70 (4H, m), 1.80-1.95 (2H, m), 3.71-3.74 (1H,m), 5.53 (1H, d, J=9 Hz), 6.90-7.10 (2H, m), 7.35-7.45 (1H, m), 7.63(2H, d, J=8 Hz) and 7.93 (2H, d, J=8 Hz). MS, m/z: Calcd, 395.137;Found, 395.59 (M).

Synthesis 24N-(cis-4-(Dimethylamino)cyclohexyl)-2′,4′-difluorobiphenyl-4-sulfonamide(ABD798)

A solution of ABD786 (200 mg, 0.55 mmol) in dry THF (5 mL) was stirredat room temperature and 2 M dimethylamine in THF (0.55 mL, 1.10 mmol)was added by syringe. The solution was cooled to 0° C. under argon andsodium triacetoxyborohydride (150 mg, 0.71 mmol) was added in oneportion. The reaction mixture was stirred at 0° C. for 1 hour and thenat room temperature overnight. TLC indicated incomplete reaction sofurther 2 M dimethylamine in THF (0.5 mL, 1 mmol) and sodiumtriacetoxyborohydride (100 mg, 0.47 mmol) were added. After a further 24hours, 2 M NaOH (3 mL) was added. The layers were separated and theaqueous phase was extracted with diethyl ether (2×10 mL). The combinedorganic solvents were dried over MgSO₄ and then evaporated to afford aviscous yellow oil. This was dissolved in MeOH (5 mL) and loaded onto a5 g SCX-2 column, which was eluted with MeOH (2×10 mL) and then with 25%2 M NH₃/MeOH in DCM (5×10 mL). The fractions containing a UV-activecomponent were combined and evaporated to afford the target compound asa pale yellow oil (230 mg, 1:1 mixture of isomers). The crude mixture ofisomers (150 mg) was separated by preparative HPLC and the titlecompound obtained as a white solid (28 mg). ¹H NMR (400 MHz, CDCl₃): δ1.15-1.31 (2H, m), 1.53-1.75 (2H, br s), 1.85 (2H, br d, J=6 Hz), 1.95(2H, br d, J=6 Hz), 2.13 (1H, br t, J=5 Hz), 2.24 (6H, s), 3.13 (1H, brt, J=5 Hz), 4.35 (1H, br s), 6.92-7.02 (2H, m), 7.44 (1H, td, J=9 Hz, 7Hz), 7.63 (2H, d, J=8 Hz) and 7.93 (2H, d, J=8 Hz). MS, m/z: Calcd,394.153; Found, 394.29 (M).

Synthesis 25N-(trans-4-(Dimethylamino)cyclohexyl)-2′,4′-difluorobiphenyl-4-sulfonamide(ABD799)

The title compound was obtained as a white solid by preparative HPLC ofthe mixture of isomers obtained in the previous synthesis. ¹H NMR (400MHz, CDCl₃): δ 1.45-1.75 (8H, m), 2.07 (1H, br s), 2.23 (6H, s), 3.45(1H, br s), 4.58 (1H, br s), 6.92-7.02 (2H, m), 7.44 (1H, td, J=9 Hz, 7Hz), 7.63 (2H, d, J=8 Hz) and 7.92 (2H, d, J=8 Hz). MS, m/z: Calcd,394.153; Found, 394.29 (M).

Synthesis 264-Bromo-3-fluoro-N-(trans-4-hydroxycyclohexyl)benzenesulfonamide(ABD665a)

Method D: 4-Bromo-3-fluorobenzene sulfonyl chloride (1 g) was dissolvedin DCM (30 mL). Trans-4-aminocyclohexanol (1 g) was added and themixture stirred overnight. Pyridine (3 mL) was added and the mixture wasstirred for 3 hours, poured into 2 M HCl and separated. The organicphase was collected and the aqueous phase washed with ethyl acetate. Thetwo organic phases were combined and the resultant solution was driedand evaporated to give an off-white residue. The residue wasrecrystallised from diethyl ether/petrol, to give the title compound asa white powder.

Synthesis 272-Fluoro-N-(trans-4-hydroxycyclohexyl)-4′-(trifluoromethoxy)biphenyl-4-sulfonamide(ABD665)

Using a method analogous to Method B, with ABD665a and4-trifluoromethoxyphenylboronic acid, the title compound was obtained asa white powder. ¹H NMR (250 MHz, DMSO-d₆): δ 1.06-1.20 (4H, m), 1.66(4H, m), 2.97 (1H, br s), 3.32 (1H, br s), 4.51 (1H, d, J=4.3 Hz), 7.52(2H, d, J=8.2 Hz), and 7.74 (6H, m).

Synthesis 282′,5′-Difluoro-N-(trans-4-hydroxycyclohexyl)biphenyl-4-sulfonamide(ABD679)

Using a method analogous to Method B, with ABD598 and2,5-difluorophenylboronic acid, the title compound was obtained as awhite powder. ¹H NMR (300 MHz, DMSO-d₆): δ 1.02-1.20 (4H, m), 1.60-1.72(4H, m), 2.94 (1H, m), 3.29 (1H, m), 4.49 (1H, d, J=4.2 Hz), 7.32 (1H,m), 7.42 (1H, m), 7.52 (1H, m), 7.73 (1H, d, J=7.2 Hz), 7.76 (2H, d,J=7.8 Hz), and 7.90 (2H, d, J=8.7 Hz). MS, m/z: Calcd, 367.11; Found,366.1 (M−1).

Synthesis 292′-Chloro-N-(trans-4-hydroxycyclohexyl)biphenyl-4-sulfonamide (ABD682)

Using a method analogous to Method B, with ABD598 and2-chlorophenylboronic acid, the title compound was obtained as a whitepowder. ¹H NMR (300 MHz, DMSO-d₆): δ 1.01-1.20 (4H, m), 1.60-1.72 (4H,m), 2.94 (1H, m), 3.29 (1H, m), 4.47 (1H, d, J=4.2 Hz), 7.45 (3H, m),7.59 (1H, m), 7.63 (2H, d, J=8.4 Hz), 7.72 (1H, m), and 7.88 (2H, d,J=8.4 Hz). MS, m/z: Calcd, 365.09; Found, 364.6 (M−1).

Synthesis 30N-(trans-4-Hydroxycyclohexyl)-3′-(trifluoromethyl)biphenyl-4-sulfonamide(ABD683)

Using a method analogous to Method B, with ABD598 and3-trifluoromethylphenylboronic acid, the title compound was obtained asa white powder. ¹H NMR (300 MHz, DMSO-d₆): δ 1.00-1.20 (4H, m),1.59-1.71 (4H, m), 2.92 (1H, m), 3.30 (1H, m), 4.47 (1H, d, J=4.2 Hz),7.68-7.78 (3H, m), 7.89 (2H, d, J=8.4 Hz), 7.97 (2H, d, J=8.4 Hz), and8.06 (2H, m). MS, m/z: Calcd, 399.11; Found, 398.5 (M−1).

Synthesis 314-Bromo-N-(trans-4-hydroxycyclohexyl)-2-(trifluoromethoxy)benzenesulfonamide(ABD684a)

Using a method analogous to Method D, with4-bromo-2-trifluoromethoxybenzene sulfonyl chloride andtrans-4-aminocyclohexanol, the title compound was obtained as a whitepowder.

Synthesis 32N-(trans-4-Hydroxycyclohexyl)-4′-methyl-3-(trifluoromethoxy)biphenyl-4-sulfonamide(ABD684)

Using a method analogous to Method B, with ABD684a and4-methylphenylboronic acid, the title compound was obtained as a whitepowder. ¹H NMR (300 MHz, DMSO-d₆): δ 1.07 (2H, m), 1.25 (2H, m), 1.63(2H, m), 1.72 (2H, m), 2.36 (3H, s), 3.05 (1H, m), 3.27 (1H, m), 4.49(1H, d, J=4.2 Hz), 7.32 (2H, d, J=8.1 Hz), 7.66 (2H, d, J=8.1 Hz), 7.69(1H, s), 7.84 (2H, m) and 7.97 (1H, d, J=8.4 Hz). MS, m/z: Calcd,429.12; Found, 428.5 (M−1).

Synthesis 332′,4′-Difluoro-N-(trans-4-hydroxycyclohexyl)-3-(trifluoromethoxy)biphenyl-4-sulfonamide(ABD689)

Using a method analogous to Method B, with ABD684a and2,4-difluorophenylboronic acid, the title compound was obtained as awhite powder. ¹H NMR (300 MHz, DMSO-d₆): δ 1.08 (2H, m), 1.23 (2H, m),1.63-1.76 (4H, m), 3.09 (1H, m), 3.31 (1H, m), 4.50 (1H, m), 7.26 (1H,t, J=8.4 Hz), 7.48 (1H, t, J=9.0 Hz), 7.65 (1H, s), 7.71 (2H, m), 7.92(1H, d, J=7.5 Hz) and 8.01 (1H, d, J=8.1 Hz). MS, m/z: Calcd, 451.09;Found, 450.5 (M−1).

Synthesis 342′,4′-Difluoro-N-(trans-4-hydroxycyclohexyl)-3-methylbiphenyl-4-sulfonamide(ABD699)

Using a method analogous to Method D, with2′,4′-difluoro-3-methylbiphenyl sulfonyl chloride andtrans-4-aminocyclohexanol, the title compound was obtained as a clearoil which solidified on standing. ¹H NMR (250 MHz, DMSO-d₆): δ 1.10 (2H,m), 1.29 (2H, m), 1.58-1.75 (4H, m), 2.62 (3H, s), 2.94 (1H, br s), 3.31(1H, br s), 4.50 (1H, s), 7.20 (1H, br t), 7.37 (1H, br t), 7.52 (2H,m), 7.63 (1H, br d), 7.72 (1H, br d) and 7.90 (1H, br d).

Synthesis 354-Bromo-N-(trans-4-hydroxycyclohexyl)-3-methylbenzenesulfonamide(ABD702a)

Using a method analogous to Method D, with 4-bromo-3-methylbenzenesulfonyl chloride and trans-4-aminocyclohexanol, the title compound wasobtained as a white powder.

Synthesis 364′-Fluoro-N-(trans-4-hydroxycyclohexyl)-2-methylbiphenyl-4-sulfonamide(ABD702)

Using a method analogous to Method B, with ABD702a and2,4-difluorophenylboronic acid, the title compound was obtained as awhite powder. ¹H NMR (300 MHz, DMSO-d₆): δ 1.05-1.21 (4H, m), 1.71 (4H,m), 2.29 (3H, s), 2.91 (1H, m), 3.30 (1H, m), 4.47 (1H, m), 7.29 (2H, t,J=9.0 Hz), 7.43 (3H, m), 7.67 (2H, m) and 7.89 (1H, s). MS, m/z: Calcd,363.13; Found, 362.73 (M).

Synthesis 374′-Cyano-N-(trans-4-hydroxycyclohexyl)-2-methylbiphenyl-4-sulfonamide(ABD703)

Using a method analogous to Method B, with ABD702a and4-cyanophenylboronic acid, the title compound was obtained as a whitepowder. ¹H NMR (300 MHz, DMSO-d₆): δ 1.05-1.21 (4H, m), 1.70 (4H, m),2.29 (3H, s), 2.93 (1H, m), 3.28 (1H, m), 4.47 (1H, d. J=4.2 Hz), 7.43(1H, d, J=8.1 Hz), 7.62 (2H, d, J=8.1 Hz), 7.68 (2H, m), 7.75 (1H, s)and 7.89 (2H, d, J=8.1 Hz). MS, m/z: Calcd, 370.14; Found, 369.7 (M).

Synthesis 384-Bromo-2-chloro-N-(trans-4-hydroxycyclohexyl)benzenesulfonamide(ABD704a)

Using a method analogous to Method D, with 4-bromo-2-chlorobenzenesulfonyl chloride and trans-4-aminocyclohexanol, the title compound wasobtained as a white powder.

Synthesis 393-Chloro-N-(trans-4-hydroxycyclohexyl)-4′-methylbiphenyl-4-sulfonamide(ABD704)

Using a method analogous to Method B, with ABD704a and4-methylphenylboronic acid, the title compound was obtained as a whitepowder. ¹H NMR (300 MHz, DMSO-d₆): δ 1.70 (2H, m), 1.88 (2H, m), 2.22(4H, m), 2.37 (3H, s), 3.57 (1H, m), 7.33 (2H, d, J=7.2 Hz), 7.70 (2H,d, J=8.1 Hz), 7.83 (1H, d, J=8.4 Hz), 7.95 (1H, s), 8.06 (1H, d, J=8.1Hz) and 8.15 (1H, d, J=7.5 Hz). MS, m/z: Calcd, 379.10; Found, 378.20(M−1).

Synthesis 403-Chloro-2′,4′-difluoro-N-(trans-4-hydroxycyclohexyl)biphenyl-4-sulfonamide(ABD705)

Using a method analogous to Method B, with ABD704a and2,4-difluorophenylboronic acid, the title compound was obtained as awhite powder. ¹H NMR (DMSO-d₆): δ 1.08 (2H, m), 1.26 (2H, m), 1.67 (4H,m), 2.99 (1H, br s), 3.28 (1H, m), 4.51 (1H, d, J=4.3 Hz), 7.24 (1H, t,J=9.1 Hz), 7.43 (1H, t, J=9.1 Hz), 7.69 (1H, d, J=7.9 Hz), 7.72 (1H, d,J=7.9 Hz), 7.81 (1H, s), 7.93 (1H, d, J=7.6 Hz) and 8.07 (1H, d, J=8.2Hz).

Synthesis 414′-Ethoxy-2-fluoro-N-(trans-4-hydroxycyclohexyl)biphenyl-4-sulfonamide(ABD706)

Using a method analogous to Method B, with ABD665a and4-ethoxyphenylboronic acid, the title compound was obtained as a whitepowder. ¹H NMR (300 MHz, DMSO-d₆): δ 1.05-1.16 (4H, m), 1.34 (3H, t,J=6.9 Hz), 1.69 (4H, m), 2.94 (1H, m), 3.29 (1H, m), 4.08 (2H, q, J=6.9Hz), 4.48 (1H, d. J=4.2 Hz), 7.05 (2H, d, J=8.7 Hz), 7.55 (2H, d, J=7.2Hz) and 7.66-7.77 (4H, m). MS, m/z: Calcd, 393.14; Found, 392.47 (M−1).

Synthesis 422-Fluoro-N-(trans-4-hydroxycyclohexyl)-4′-methoxybiphenyl-4-sulfonamide(ABD710)

Using a method analogous to Method B, with ABD665a and4-methoxyphenylboronic acid, the title compound was obtained as a whitepowder. ¹H NMR (DMSO-d₆): δ 1.15 (4H, m), 1.70 (4H, m), 2.99 (1H, br s),3.32 (1H, m), 3.81 (3H, s), 4.50 (1H, s), 7.06 (2H, d, J=7.9 Hz), 7.55(2H, d, J=7.9 Hz), 7.70 (3H, m) and 7.82 (1H, d, J=7.9 Hz).

Synthesis 434′-Chloro-N-(trans-4-hydroxycyclohexyl)-3′-(trifluoromethyl)biphenyl-4-sulfonamide(ABD712)

Using a method analogous to Method B, with ABD598 and4-chloro-3-trifluoromethylphenylboronic acid, the title compound wasobtained as a white powder. ¹³C NMR (DMSO-d₆): δ 31.1, 33.6, 51.8, 67.6,126.8, 127.1, 127.3, 127.6, 127.9, 130.8, 132.5, 138.1, 140.8, and142.0. ¹H NMR (DMSO-d₆): δ 1.05-1.22 (4H, m), 1.70 (4H, m), 2.93 (1H, brs), 3.32 (1H, br s), 4.51 (1H, d, J=4.0 Hz), 7.75 (1H, d, J=7.0 Hz),7.82 (1H, d, J=8.5 Hz), 7.91 (2H, d, J=8.5 Hz), 7.97 (2H, d, J=7.6 Hz),8.05 (1H, d, J=7.9 Hz) and 8.12 (1H, s).

Synthesis 442-Fluoro-N-(trans-4-hydroxycyclohexyl)-4′-(trifluoromethyl)biphenyl-4-sulfonamide(ABD714)

Using a method analogous to Method B, with ABD665a and4-trifluoromethylphenylboronic acid, the title compound was obtained asa white powder. ¹H NMR (300 MHz, DMSO-d₆): δ 1.05-1.17 (4H, m), 1.68(4H, m), 2.96 (1H, m), 3.29 (1H, m), 4.49 (1H, d. J=4.2 Hz) and7.59-7.87 (7H, m). MS, m/z: Calcd, 417.10; Found, 416.3 (M−1).

Synthesis 454′-Acetyl-3-chloro-N-(trans-4-hydroxycyclohexyl)biphenyl-4-sulfonamide(ABD716)

Using a method analogous to Method B, with ABD704a and4-acetylphenylboronic acid, the title compound was obtained as a whitepowder. ¹H NMR (300 MHz, DMSO-d₆): δ 1.06 (2H, m), 1.23 (2H, m),1.63-1.76 (4H, m), 2.62 (3H, s), 2.97 (1H, m), 3.28 (1H, m), 4.48 (1H,d, J=4.2 Hz), 7.90 (2H, m), 7.95 (2H, d, J=8.4 Hz), 8.04 (2H, m) and8.07 (2H, d, J=9.0 Hz). MS, m/z: Calcd, 407.10; Found, 406.5 (M−1),408.3 (M+1).

Synthesis 464-Bromo-2-ethyl-N-(trans-4-hydroxycyclohexyl)benzenesulfonamide(ABD730a)

Using a method analogous to Method D, with 4-bromo-2-ethylbenzenesulfonyl chloride and trans-4-aminocyclohexanol, the title compound wasobtained as a white powder.

Synthesis 473-Ethyl-2′,4′-difluoro-N-(trans-4-hydroxycyclohexyl)biphenyl-4-sulfonamide(ABD730)

Using a method analogous to Method B, with ABD730a and2,4-difluorophenylboronic acid, the title compound was obtained as awhite powder. ¹H NMR (300 MHz, DMSO-d₆): δ 1.08 (2H, m), 1.23 (2H, m),1.25 (3H, t, J=7.3 Hz), 1.68 (4H, m), 2.97 (1H, m), 3.01 (2H, q, J=7.3Hz), 3.26 (1H, m), 4.48 (1H, d, J=4.5 Hz), 7.23 (1H, t, J=8.4 Hz), 7.43(1H, t, J=9.0 Hz), 7.53 (1H, d, J=8.1 Hz), 7.56 (1H, s), 7.63 (1H, m),7.75 (1H, d, J=7.8 Hz) and 7.92 (1H, d, J=8.1 Hz). MS, m/z: Calcd,395.14; Found, 394.3 (M−1).

Synthesis 483-Chloro-4′-cyano-N-(trans-4-hydroxycyclohexyl)biphenyl-4-sulfonamide(ABD732)

Using a method analogous to Method B, with ABD704a and4-cyanophenylboronic acid, the title compound was obtained as a whitepowder. ¹³C NMR (DMSO-d₆): δ 31.0, 33.7, 51.9, 67.7, 111.6, 118.6,126.3, 128.2, 130.2, 131.2, 131.5, 133.0, 138.8, 141.5 and 143.2. ¹H NMR(DMSO-d₆): δ 1.03 (2H, m), 1.31 (2H, m), 1.67 (4H, m), 2.97 (1H, br s),3.30 (1H, br s), 4.51 (1H, d, J=4.0 Hz) and 7.87-8.10 (8H, m).

Synthesis 492′,4′-Difluoro-N-(trans-4-hydroxycyclohexyl)-2-methylbiphenyl-4-sulfonamide(ABD735)

Using a method analogous to Method B, with ABD702a and2,4-difluorophenylboronic acid, the title compound was obtained as awhite powder. ¹H NMR (DMSO-d₆): δ 1.11 (4H, m), 1.68 (4H, m), 2.20 (3H,s), 2.93 (1H, br s), 3.32 (1H, br s), 4.50 (1H, s), 7.19 (1H, m), 7.39(1H, m), 7.40 (2H, d, J=8.2 Hz), 7.69 (2H, m) and 7.77 (1H, s). ¹³C NMR(DMSO-d₆): δ 19.6, 31.1, 33.6, 51.7, 67.6, 104.2 (m), 111.9 (m), 123.4,123.7, 127.5 (dd, J=14.7, 8.7 Hz), 130.9, 132.7, 137.5, 138.0, 142.0,158.8 (dd, J=246.1, 11.7 Hz) and 162.0 (dd, J=250.0, 13.7 Hz). MS, m/z:Calcd, 381.12; Found, 380.7 (M).

Synthesis 50N-(trans-4-Hydroxycyclohexyl)-2-methyl-4′-(trifluoromethoxy)biphenyl-4-sulfonamide(ABD742)

Using a method analogous to Method B, with ABD702a and4-trifluoromethoxyphenylboronic acid, the title compound was obtained asa white powder. ¹H NMR (250 MHz, DMSO-d₆): δ 1.06-1.22 (4H, m), 1.70(4H, m), 2.30 (3H, s), 2.94 (1H, br s), 3.31 (1H, br s), 4.51 (1H, d,J=4.3 Hz), 7.43 (3H, m), 7.53 (2H, d, J=8.5 Hz), 7.69 (2H, m) and 7.76(1H, s). ¹³C NMR (250 MHz, DMSO-d₆): δ 20.2, 31.1, 33.6, 51.7, 67.6,120.9, 123.9, 128.0, 130.4, 130.9, 136.2, 139.1, 141.4, 143.4 and 147.9.

Synthesis 512′,4′-Dichloro-N-(trans-4-hydroxycyclohexyl)-3-(trifluoromethoxy)biphenyl-4-sulfonamide(ABD756)

Using a method analogous to Method B, with ABD684a and2,4-dichlorophenylboronic acid, the title compound was obtained as awhite powder. ¹H NMR (250 MHz, DMSO-d₆): δ 1.10 (2H, m), 1.27 (2H, m),1.69 (4H, m), 3.08 (1H, br s), 3.32 (1H, br s), 4.52 (1H, d. J=4.3 Hz),7.58 (3H, m), 7.62 (1H, d, J=8.2 Hz), 7.80 (1H, s), 7.93 (1H, br d) and8.02 (1H, d, J=7.9 Hz).

Synthesis 52Ethyl-cis-2-(2′,4′-difluorobiphenyl-4-ylsulfonamido)cyclopentanecarboxylate (ABD769a)

Ethyl cis-2-aminocyclopentanecarboxylate hydrochloride (390 mg, 2.0mmol) and 2′,4′-difluorobiphenylsulfonyl chloride (480 mg, 1.67 mmol)were stirred in DCM (5 mL) and pyridine (400 μL) was added. The mixturewas stirred at room temperature overnight, after which TLC indicatedboth starting materials were still present. DMAP (10 mg) and additionalpyridine (1 mL) were added and stirring was continued for a further 24hours, when TLC indicated no starting materials remained and a newcompound had formed. The reaction mixture was diluted with DCM (10 mL)and water (5 mL) and conc. HCl (1.5 mL) was added and the mixture wasstirred for 10 minutes. The layers were separated and the DCM was washedwith water (2×5 mL), dried (hydrophobic membrane) and evaporated. Thecrude product was purified by chromatography on SiO₂ (70 g (solute IIcartridge, SP4), eluting with 0-40% acetone/hexane to give the titlecompound as a pale yellow solid (410 mg, 60%).

Synthesis 532′,4′-Difluoro-N-(cis-2-(hydroxymethyl)cyclopentyl)biphenyl-4-sulfonamide(ABD769)

A solution of ABD769a (100 mg, 0.24 mmol) in dry THF (5 mL) was cooledunder argon to 0° C. and LiAlH₄ (1 M in THF, 1.22 mL, 1.22 mmol) wasadded by syringe. The ice bath was removed after 15 minutes and thesolution was stirred overnight at room temperature. The mixture was thencooled back to 0° C. and dry THF (10 mL) was added, followed byNa₂SO₄.10H₂O (˜1 g). The suspension was stirred for 1 hour at roomtemperature and then filtered. Evaporation of the solvents afforded acolourless glassy solid, which was triturated with ether and hexane atlow temperature to give the title compound as a white powder (64 mg,73%). ¹H NMR (300 MHz, DMSO-d₆): δ 1.20-1.65 (6H, m), 1.89 (1H, br s),3.15-3.25 (1H, m), 3.43-3.58 (2H, m), 7.21 (1H, t, J=8 Hz), 7.40 (1H, t,J=10 Hz), 7.64 (1H, q, J=8 Hz), 7.70 (2H, d, J=8 Hz) and 7.86 (2H, d,J=8 Hz).

Synthesis 54N-(cis-4-Aminocyclohexyl)-2′,4′-difluorobiphenyl-4-sulfonamide (ABD812)

N-(cis-4-(2,4-Dimethoxybenzylamino)cyclohexyl)-2′,4′-difluorobiphenyl-4-sulfonamide(see ABD787a) (52 mg, 0.10 mmol) was stirred in acetonitrile (3 mL) andwater (1 mL) and ceric ammonium nitrate (144 mg, 0.26 mmol) was added.The mixture was stirred at 50° C. overnight and then diluted with EtOAc(15 mL) and washed with water (2×5 mL). The washings were extracted withEtOAc (5 mL) and the combined organics were dried over MgSO₄. Afterevaporation of the solvents, the residue was loaded onto a 1 g SCXcolumn and eluted with MeOH and then 20% 2 M NH₃/MeOH in DCM. Theresulting material was further purified by chromatography (2 g (soluteII cartridge), eluting with 0-10% 2 M NH₃/MeOH in DCM to afford thetitle compound as an off-white powder (9 mg, 25%). ¹H NMR (300 MHz,DMSO-d₆): δ 0.86-0.98 (2H, m), 1.09-1.26 (2H, m), 1.55-1.68 (4H, m),2.40 (1H, br s), 2.87 (1H, br s), 4.12 (1H, br s), 7.22 (1H, td, J=8 Hz,2 Hz), 7.40 (1H, td, J=10 Hz, 2.5 Hz), 7.65 (1H, q, J=7 Hz), 7.71 (2H,d, J=9 Hz) and 7.85 (2H, d, J=9 Hz). LCMS: (MH)⁺=367.

Synthesis 55 (1S,3S)-Methyl3-(2′,4′-difluorobiphenyl-4-ylsulfonamido)cyclopentane carboxylate(ABD813a)

Using a method analogous to Method A, with methyl(1S,3S)-3-aminocyclopentanecarboxylate hydrochloride and2′,4′-difluorobiphenylsulfonyl chloride, the title compound was obtainedas a pale yellow solid (61%).

Synthesis 562′,4′-Difluoro-N-((1S,3S)-3-(hydroxymethyl)cyclopentyl)biphenyl-4-sulfonamide(ABD813)

A solution of ABD813a (105 mg, 0.27 mmol) in dry THF (5 mL) was cooledunder argon to 0° C. and LiAlH₄ (1 M in THF, 1.33 mL, 1.33 mmol) wasadded by syringe. After 5 minutes the ice bath was removed and thesolution was stirred at room temperature for 2 hours. After cooling backto 0° C., the reaction was quenched by adding Na₂SO₄10.H₂O (˜500 mg)cautiously. Once bubbling had stopped the mixture was diluted with EtOAc(10 mL) and stirred for 1 hour at room temperature before beingfiltered, rinsing the solids well with EtOAc. Evaporation of the solventafforded the crude product as a colourless glassy solid which waspurified by repeated chromatography on SiO₂ (acetone/hexane) and finallytrituration with Et₂O, to give the title compound as a white powder (6mg, 6%). ¹H NMR (300 MHz, CDCl₃): δ 1.20-1.52 (3H, m), 1.60-1.73 (2H,m), 1.76-1.90 (2H, m), 2.24 (1H, quintet, J=7 Hz), 3.48 (2H, br s), 3.71(1H, q, J=6 Hz), 4.56 (1H, d, J=7 Hz), 6.94-7.00 (2H, m), 7.43 (1H, q,J=7 Hz), 7.64 (2H, d, J=8 Hz) and 7.93 (2H, d, J=8 Hz). LCMS: (MH)⁺=368.

Synthesis 572′,4′-Difluoro-N-((1S,3S)-3-(2-hydroxypropan-2-yl)cyclopentyl)biphenyl-4-sulfonamide(ABD815)

A solution of ABD813a (105 mg, 0.27 mmol) in dry THF (5 mL) was cooledunder argon to 0° C. and MeMgBr (3 M in Et₂O, 440 μL, 1.33 mmol) wasadded by syringe and the solution was stirred for 2 hours. TLC indicatedsome starting material remaining, and so further MeMgBr (3 M in Et₂O,440 μL, 1.33 mmol) was added and stirring continued at room temperaturefor a further 2 hours. The mixture was diluted with Et₂O (30 mL) andquenched with NH₄Cl (sat. aq., 10 mL). The layers were separated and theaqueous phase was extracted with further Et₂O (10 mL) and the combinedorganics were washed with brine (10 mL) and dried over MgSO₄. Afterevaporation of the solvent the crude product was purified bychromatography on SiO₂ (20% acetone/hexane) to give the title compoundas a colourless gum (77 mg, 72%). ¹H NMR (300 MHz, CDCl₃): δ 1.12 (3H,s), 1.13 (3H, s), 1.45-1.75 (6H, m), 1.84-1.97 (1H, m), 2.07 (1H, t, J=8Hz), 3.68 (1H, q, J=5 Hz), 4.60 (1H, d, J=7 Hz), 6.94-7.00 (2H, m), 7.42(1H, td, J=8 Hz, 6 Hz), 7.64 (2H, dd, J=8 Hz, 2 Hz) and 7.93 (2H, d, J=8Hz). LCMS: (MH)⁺=396.

Synthesis 582′,4′-Difluoro-N-(4-(methylamino)cyclohexyl)biphenyl-4-sulfonamide(ABD816)

A solution of ABD786 (250 mg, 0.68 mmol) in dry THF (5 mL) was stirredunder argon and methylamine (2 M in THF, 1.35 mL) was added by syringe.The solution was stirred for 1 hour and then STAB (360 mg, 1.7 mmol) wasadded in one portion. The mixture was stirred at room temperatureovernight. TLC indicated starting material to still be present, and sofurther methylamine (2 M in THF, 1.35 mL) and STAB (360 mg, 1.7 mmol)and a drop of acetic acid were added and stirring was continued for afurther 3 days. The reaction was quenched by the addition of 2 M NaOH(aq., 4 mL) and Et₂O (20 mL) and the layers were separated. The aqueousphase was extracted with Et₂O (5 mL) and the combined organics werewashed with water (2×5 mL) and dried over MgSO₄. After evaporation ofthe solvents, the crude product was purified by catch-and-release on a 5g SCX cartridge, eluting with MeOH and then 25% 2 M NH₃/MeOH in DCM, toafford the crude amine. This was further purified by columnchromatography (10 g (solute II cartridge), eluting with 5%-10% 2 MNH₃/MeOH in DCM and finally by trituration with ether and petrol to givethe title compound as a white powder (˜1:1 mixture of stereoisomers) (93mg, 36%). ¹H NMR (300 MHz, DMSO-d₆): δ 0.80-1.80 (8H, m), 2.08 (0.5H, brs), 2.16 (3H, s), 2.30 (0.5H, br s), 2.90 (0.5H, br s), 3.03 (0.5H, brs), 4.84 (0.5H, br d, J=6 Hz), 7.21 (1H, t, J=8 Hz), 7.39 (1H, t, J=9Hz), 7.64 (1H, q, J=7 Hz), 7.70 (2H, d, J=9 Hz) and 7.86 (2H, d, J=9Hz). LCMS: (MH)⁺=381.

Synthesis 59N-(4-(Ethylamino)cyclohexyl)-2′,4′-difluorobiphenyl-4-sulfonamide(ABD817)

A solution of ABD786 (250 mg, 0.68 mmol) in dry THF (5 mL) was stirredunder argon and ethylamine (2 M in THF, 1.35 mL) was added by syringe.The solution was stirred for 1 hour and then STAB (360 mg, 1.7 mmol) wasadded in one portion. The mixture was stirred at room temperatureovernight. TLC indicated starting material to still be present, and sofurther ethylamine (2 M in THF, 1.35 mL) and STAB (360 mg, 1.7 mmol) anda drop of acetic acid were added and stirring was continued for afurther 3 days. The reaction was quenched by the addition of 2 M NaOH(aq., 4 mL) and Et₂O (20 mL) and the layers were separated. The aqueousphase was extracted with Et₂O (5 mL) and the combined organics werewashed with water (2×5 mL) and dried over MgSO₄. After evaporation ofthe solvents, the crude product was purified by catch-and-release on a 5g SCX cartridge, eluting with MeOH and then 25% 2 M NH₃/MeOH in DCM, toafford the crude amine. This was further purified by columnchromatography (10 g Isolute II cartridge), eluting with 5%-10% 2 MNH₃/MeOH in DCM and finally by trituration with ether and petrol to givethe title compound as a white powder (˜1:1 mixture of stereoisomers) (95mg, 35%). ¹H NMR (300 MHz, DMSO-d₆): δ 0.88-0.97 (3H, m), 1.08-1.63 (8H,m), 1.75 (1H, d, J=11 Hz), 2.19 (1H, br s), 2.42 (2H, q, J=7 Hz), 2.90(0.5H, br s), 3.04 (0.5H, br s), 7.21 (1H, td, J=8 Hz, 2 Hz), 7.40 (1H,td, J=10 Hz, 2 Hz), 7.64 (1H, q, J=7 Hz), 7.70 (2H, d, J=9 Hz), 7.85(1H, d, J=9 Hz) and 7.87 (1H, d, J=9 Hz). LCMS: (MH)⁺=395.

Synthesis 602′,4′-Difluoro-N-(4-(isopropylamino)cyclohexyl)biphenyl-4-sulfonamide(ABD818)

ABD786 (450 mg, 1.23 mmol) was stirred in DCM (5 mL) and ^(i)PrNH₂ (160μL, 110 mg, 1.85 mmol) was added and the solution was stirred overnightat room temperature. It was then diluted with further DCM (5 mL) andSTAB (1.30 g, 6.15 mmol) was added and stirring was continued for 2hours. 2 M NaOH (aq., 7 mL) and EtOAc (30 mL) were added and the mixturewas stirred for a further 30 minutes before the layers were separated.The aqueous phase was extracted with further EtOAc (10 mL) and thecombined organics were washed with water (2×10 mL) and brine (10 mL) anddried over MgSO₄. After evaporation of the solvents the crude productwas split into two portions and each was purified by catch and releasechromatography on a 2 g SCX cartridge, eluting with MeOH and then 10% 2M NH₃/MeOH in DCM, affording the desired material as a red-brown glassysolid. This was triturated with Et₂O at 0° C. to give the title compoundas an off-white powdery solid (200 mg, 40%, highly enriched (7:1) in oneisomer). The trituration solvents were evaporated and the residue waspurified by chromatography on SiO₂ (10 g Isolute II cartridge), elutingwith 10% 2 M NH₃/MeOH in DCM to afford a pale yellow glassy solid,trituration of which with ether and hexane afforded a second crop of thetitle compound as an off-white powdery solid (78 mg, 15%, 4:6 mixture ofisomers). ¹H NMR (second crop) (300 MHz, DMSO-d₆): δ 0.86 (3H, d, J=7.5Hz), 0.90 (3H, d, J=7.5 Hz), 1.15 (1H, q, J=15 Hz), 1.28-1.41 (4H, m),1.47-1.55 (1H, m), 1.66 (1H, d, J=13 Hz), 1.70 (1H, d, J=15 Hz),2.25-2.33 (0.6H, m), 2.51-2.55 (0.4H, m), 2.74 (1H, octet, J=7.5 Hz),2.89 (0.4H, br s), 3.05 (0.6H, br s), 7.21 (1H, td, J=11 Hz, 3 Hz), 7.40(1H, ddd, J=14 Hz, 11 Hz, 3 Hz), 7.63 (1H, t, J=10 Hz), 7.70 (2H, d, J=9Hz), 7.85 (1.2H, d, J=10 Hz) and 7.87 (0.8H, d, J=10 Hz). LCMS:(MH)⁺=409.

Synthesis 61N-(4-(Diethylamino)cyclohexyl)-2′,4′-difluorobiphenyl-4-sulfonamide(ABD819)

Prepared in an analogous fashion to ABD817, using diethylamine, to givethe title compound as an off-white powder (˜1:1 mixture ofstereoisomers) (168 mg, 58%). ¹H NMR (300 MHz, DMSO-d₆): δ 0.84-0.89(6H, m), 1.05-1.75 (8H, m), 2.35 (4H, q, J=7 Hz), 2.90 (0.5H, br s),3.20 (0.5H, br s), 7.21 (1H, td, J=8 Hz, 2 Hz), 7.41 (1H, ddd, J=12 Hz,9 Hz, 3 Hz), 7.60-7.65 (1H, m), 7.71 (2H, d, J=9 Hz) and 7.84-7.89 (2H,m). LCMS: (MH)⁺=423.

Synthesis 622′,4′-Difluoro-N-(4-(pyrrolidin-1-yl)cyclohexyl)biphenyl-4-sulfonamide(ABD820)

Prepared in an analogous fashion to ABD817, using pyrrolidine, to givethe title compound as an off-white powder (˜2:3 mixture ofstereoisomers) (26 mg, 9%). ¹H NMR (400 MHz, DMSO-d₆): δ 1.00-1.47 (6H,m), 1.60-1.65 (4H, m), 1.79-2.01 (3H, m), 2.48 (4H, br s), 2.93 (0.5H,br s), 3.07 (0.5H, br s), 7.21 (1H, td, J=8 Hz, 2 Hz), 7.40 (1H, ddd,J=12 Hz, 9 Hz, 3 Hz), 7.61-7.66 (1H, m), 7.70 (2H, d, J=9 Hz) and7.84-7.89 (2H, m). LCMS: (MH)⁺=421.

Synthesis 632′,4′-Difluoro-N-(4-morpholinocyclohexyl)biphenyl-4-sulfonamide (ABD821)

Prepared in an analogous fashion to ABD817, using morpholine, to givethe title compound as an off-white powder (˜3:2 mixture ofstereoisomers) (63 mg, 21%). ¹H NMR (300 MHz, DMSO-d₆): δ 1.11 (2H, q,J=8 Hz), 1.25-1.42 (2H, m), 1.51-1.60 (2H, m), 1.67 (2H, d, J=9 Hz),2.02 (1H, br s), 2.34-2.38 (4H, m), 2.90 (0.5H, br s), 3.15 (0.5H, brs), 3.45-3.52 (4H, m), 7.21 (1H, td, J=8 Hz, 2 Hz), 7.40 (1H, ddd, J=12Hz, 9 Hz, 3 Hz), 7.64 (1H, q, J=8 Hz), 7.70 (2H, d, J=9 Hz), 7.86 (1H,d, J=8 Hz) and 7.87 (1H, d, J=8 Hz). LCMS: (MH)⁺=437; (M−H)⁻=435.

Synthesis 64N-(4-(Ethyl(methyl)amino)cyclohexyl)-2′,4′-difluorobiphenyl-4-sulfonamide(ABD822)

Prepared in an analogous fashion to ABD817, using N-ethylmethylamine, togive the title compound as an off-white powder (˜7:3 mixture ofstereoisomers) (73 mg, 26%). ¹H NMR (400 MHz, DMSO-d₆): δ 0.88-0.91 (3H,m), 1.13-1.17 (2H, m),1.29-1.36 (2H, m), 1.52-1.66 (4H, m), 2.06 (2H, s[Me of major isomer]), 2.13 (1H, s [Me of minor isomer]), 2.26 (1H, brs), 2.37 (2H, q, J=9 Hz), 2.89 (1H, br s), 3.18 (1H, br s), 7.21 (1H, t,J=10 Hz), 7.39 (1H, t, J=12 Hz), 7.63 (1H, q, J=8 Hz), 7.70 (2H, d, J=9Hz) and 7.82-7.89 (2H, m). LCMS: (MH)⁺=409.

Synthesis 65cis-4-(2′,4′-Difluorobiphenyl-4-ylsulfonamido)cyclohexanecarboxylic acid(ABD824b)

A mixture of (ABD781a) (1.06 g, 2.6 mmol), MeOH (5 mL), THF (5 mL) andwater (5 mL) was stirred at room temperature and LiOH.H₂O (550 mg, 13mmol) was added. The mixture was stirred overnight before the MeOH andTHF were removed under reduced pressure. The residue was diluted to 40mL with water and acidified with 2 M HCl (aq.). The resulting suspensionwas stirred vigorously for 1 hour and the off-white solid was thencollected by suction and air-dried to give the title compound (920 mg,89%).

Synthesis 66cis-4-(2′,4′-Difluorobiphenyl-4-ylsulfonamido)-N-methylcyclohexanecarboxamide (ABD824a)

A suspension of ABD824b (920 mg, 2.33 mmol) in dry DCM (15 mL) wascooled under argon to 0° C. and (COCl)₂ (245 μL, 325 mg, 2.56 mmol) wasadded, followed by DMF (30 μL, catalytic). The ice bath was removed andthe mixture was stirred at room temperature for 1.5 hours, giving a paleyellow solution. A solution of methylamine (2 M in THF, 5.8 mL, 11.6mmol) in dry DCM (15 mL) was cooled under argon to 0° C. and thesolution of the acid chloride was added by cannula, resulting in theformation of a precipitate. The mixture was stirred for 1 hour, allowingit to warm to room temperature, and then diluted with further DCM (30mL) and washed with water (2×10 mL) and brine (10 mL). The organicsolvents were dried over MgSO₄ and evaporated to give the title compoundas a pale yellow solid (890 mg, 94%), which required no furtherpurification. ¹H NMR (300 MHz, CDCl₃): δ 1.48-1.78 (8H, m), 2.05-2.15(1H, m), 2.78 (3H, d, J=5 Hz), 3.48-3.57 (1H, m), 4.97 (1H, br s), 5.49(1H, br s), 6.87-7.05 (2H, m), 7.40 (1H, q, J=5 Hz), 7.64 (2H, d, J=9Hz) and 7.94 (2H, d, J=9 Hz). LCMS: (MH)⁺=409; (M−H)⁻=407.

Synthesis 672′,4′-Difluoro-N-(cis-4-((methylamino)methyl)cyclohexyl)biphenyl-4-sulfonamide(ABD824)

A solution of ABD824a (240 mg, 0.59 mmol) in dry THF (10 mL) was cooledto 0° C. under argon and BH₃ (1 M in THF, 1.8 mL, 1.8 mmol) was added bysyringe. The solution was stirred overnight, allowing it to warm to roomtemperature, after which TLC indicated that starting material was stillpresent, as well as a more polar compound. Further BH₃ (1 M in THF, 1.0mL, 1.0 mmol) was added and the solution was heated at reflux for 3hours. After cooling to room temperature, the reaction was quenched withNH₄Cl (sat. aq., 5 mL) and water was added to dissolve the solids. Themixture was extracted with Et₂O (3×15 mL) and the organics were driedover MgSO₄ and evaporated to afford the crude product as a colourlessglass. This was purified by SCX catch-and-release chromatography,eluting with MeOH and then 10% 2 M NH₃/MeOH in DCM, and finally bytrituration with Et₂O to give the title compound as a white powder (81mg, 35%). ¹H NMR (300 MHz, DMSO-d₆): δ 1.20-1.53 (8H, m), 2.22 (3H, s),2.31 (2H, d, J=7 Hz), 3.17 (2H, br s), 7.21 (1H, td, J=11 Hz, 3 Hz),7.40 (1H, ddd, J=14 Hz, 11 Hz, 3 Hz), 7.64 (1H, td, J=11 Hz, 8 Hz), 7.70(2H, d, J=9 Hz) and 7.87 (2H, d, J=10 Hz). LCMS: (MH)⁺=395.

Synthesis 68 cis-4-(2′,4′-Difluorobiphenyl-4-ylsulfonamido)-N,N-dimethylcyclohexanecarboxamide (ABD826a)

A suspension of ABD824b (850 mg, 2.15 mmol) in dry DCM (15 mL) wascooled under argon to 0° C. and (COCl)₂ (225 μL, 300 mg, 2.4 mmol) wasadded, followed by DMF (30 μL, catalytic). The ice bath was removed andthe mixture was stirred at room temperature for 1 hour, giving a paleyellow solution. Half of the solution of the acid chloride was cooled to0° C. under argon and dimethylamine (2 M in THF, 2.5 mL, 5 mmol) wasadded by syringe. The mixture was stirred overnight, allowing it to warmto room temperature. It was then diluted with further DCM (20 mL) andwashed with water (3×5 mL) and brine (5 mL). The organic solvents weredried over MgSO₄ and evaporated to afford the crude product as anoff-white solid. This was purified by chromatography on SiO₂ (20 gIsolute II cartridge), eluting with 50% acetone/hexane, to give thetitle compound as a white solid (395 mg, 87%). ¹H NMR (300 MHz, CDCl₃):δ 1.45-1.62 (4H, m), 1.65-1.82 (4H, m), 2.48-2.59 (1H, m), 2.99 (3H, s),3.00 (3H, s), 3.55-3.63 (1H, m), 5.17 (1H, d, J=8 Hz), 6.87-7.03 (2H,m), 7.42 (1H, q, J=5 Hz), 7.61 (2H, d, J=9 Hz) and 7.95 (2H, d, J=9 Hz).LCMS: (MH)⁺=423; (M−H)⁻=421.

Synthesis 69N-(cis-4-((Dimethylamino)methyl)cyclohexyl)-2′,4′-difluorobiphenyl-4-sulfonamide(ABD826)

A solution of ABD826a (200 mg, 0.47 mmol) in dry THF (5 mL) was cooledunder argon to 0° C. and LiAlH₄ (1 M in THF, 2.36 mL, 2.36 mmol) wasadded dropwise by syringe over ˜2 minutes. Once gas evolution ceased,the mixture was allowed to warm to room temperature and stirred for 1hour. The solution was then cooled back to 0° C. and quenched withNa₂SO₄.10H₂O (s, ˜500 mg) and allowed to stir overnight. The mixture wasfiltered, rinsing the solid well with additional THF. After evaporationof the solvents the crude product was purified by trituration withEt₂O/hexane, to give the title compound as a white powder (95 mg, 49%).¹H NMR (400 MHz, DMSO-d₆): δ 1.18-1.47 (8H, m), 1.97 (2H, d, J=9 Hz),2.03 (6H, s), 3.18 (2H, br s), 4.34 (1H, br s), 7.21 (1H, t, J=9 Hz),7.39 (1H, t, J=11 Hz), 7.58-7.67 (2H, m), 7.70 (2H, d, J=10 Hz) and 7.87(2H, d, J=10 Hz). LCMS: (MH)⁺=409.

Synthesis 70 4-(N-(trans-4-Hydroxycyclohexyl)sulfamoyl)phenylboronicacid (ABD836a)

ABD598 (500 mg, 1.5 mmol), bis(pinacolato)diboron (420 mg, 1.65 mmol),KOAc (294 mg, 3 mmol) and Pd(dppf)Cl₂ (55 mg, 0.08 mmol) were combinedin DMSO (10 mL) and placed in an ultrasonic bath under a stream of argonfor 5 minutes. The flask was then placed in an oil bath at 90° C. andstirred for 1 hour. The reaction mixture was then cooled to roomtemperature and poured into water (40 mL) and extracted with EtOAc (3×20mL). The combined organics were washed with water (20 mL) and brine (10mL), dried (Na₂SO₄) and filtered. Evaporation gave a brown solid (555mg), containing both the boronic acid and the ester, which was usedwithout further purification.

Synthesis 714-(3,5-Dichloropyridin-2-yl)-N-(trans-4-hydroxycyclohexyl)benzenesulfonamide (ABD836)

ABD836a (278 mg, 0.92 mmol) was dissolved in DME (4 mL) and2-bromo-3,5-dichloropyridine (171 mg, 0.76 mmol), Pd(dppf)Cl₂ (23 mg, 5mol %) and Na₂CO₃ (2 M soln, 1.15 mL, 2.30 mmol) were added. The mixturewas placed in an ultrasonic bath under a stream of argon for 5 minutes.It was then placed in a preheated oil bath (90° C.) for 1.75 hours.After this time, the reaction mixture was cooled to room temperature andpoured into water (80 mL) and extracted with EtOAc (3×60 mL). Thecombined organics were washed with water (50 mL) and brine (50 mL),dried (Na₂SO₄), filtered and evaporated onto silica. The crude materialwas purified by flash column chromatography on SiO₂, eluting with 2:1EtOAc/hexane. Evaporation of the desired fractions andre-crystallisation (DCM-hexane) gave the title compound as colourlessneedles (21 mg, 7%). ¹H NMR (300 MHz, CDCl₃): δ 1.20-1.34 (4H, m), 1.38(1H, d, J=4 Hz), 1.91 (4H, d, J=8 Hz), 3.18 (1H, br s), 3.56 (1H, br s),4.46 (1H, d, J=7.5 Hz), 7.85 (2H, d, J=8 Hz), 7.97 (3H, s overlappedwith d, J=8 Hz) and 8.58 (1H, d, J=2 Hz). LCMS: (MH)⁺=401.

Synthesis 724-(5-Chloropyrimidin-2-yl)-N-(trans-4-hydroxycyclohexyl)benzenesulfonamide(ABD837)

A solution ABD836a (278 mg, 0.92 mmol) in DME (4 mL) was stirred and2,5-dichloropyrimidine (112 mg, 0.76 mmol), Pd(dppf)Cl₂ (23 mg, 5 mol %)and Na₂CO₃ (2 M soln, 1.15 mL, 2.30 mmol) were added. The mixture wasplaced in an ultrasonic bath under a stream of argon for 5 minutes. Itwas then placed in a preheated oil bath (90° C.) for 1 hour. After thistime, the reaction mixture was cooled to room temperature and pouredinto water (80 mL) and extracted with EtOAc (3×60 mL). The combinedorganics were washed with water (50 mL), brine (50 mL), dried (Na₂SO₄),filtered and absorbed onto silica. The crude material was purified byflash column chromatography, eluting with 1:1 v/v acetone-hexane.Evaporation of the desired fractions and washing the solid with diethylether gave the title compound (55 mg, 20%) as an off-white solid. ¹H NMR(300 MHz, DMSO-d₆): δ 1.08 (4H, septet, J=11 Hz), 1.55 (2H, d, J=11 Hz),1.66 (2H, d, J=11 Hz), 2.90 (1H, t, J=9 Hz), 3.20-3.28 (1H, br m), 4.45(1H, br s), 7.74 (1H, br s), 7.93 (2H, d, J=8 Hz), 8.48 (2H, d, J=8 Hz)and 9.04 (2H, s). LCMS: (MH)⁺=368.

Synthesis 73N-(trans-4-Hydroxycyclohexyl)-4-(pyrimidin-5-yl)benzenesulfonamide(ABD861)

A solution of ABD836a (225 mg, 0.78 mmol) in DME (4 mL) was stirred atroom temperature and 5-bromopyrimidine (99 mg, 0.63 mmol), Pd(dppf)Cl₂(23 mg, 0.03 mmol) and Na₂CO₃ (2 M aq., 0.95 mL) were added. The mixturewas placed in an ultrasonic bath under a stream of argon for 5 minutesand then in an oil bath that had been pre-heated to 90° C. The reactionmixture was heated for 1 hour and then cooled to room temperature,diluted with water (20 mL) and extracted with EtOAc (3×10 mL). Theextracts were washed with water (5 mL) and brine (5 mL) and dried overMgSO₄. After evaporation of the solvents the residue was purified bycolumn chromatography on SiO₂ (50% acetone/hexane) to afford a mixtureof the desired material and a dimeric species produced during boronicacid formation. The partially purified material was triturated with Et₂O(2×2 mL) and then purified by a second SiO₂ column, this time elutingwith 5%-10% 2 M NH₃/MeOH in DCM, to give the title compound as anoff-white solid (65 mg, 31%). ¹H NMR (300 MHz, DMSO-d₆): δ 1.10 (4H,septet, J=7 Hz), 1.55-1.73 (4H, m), 2.85-2.95 (1H, m), 3.20-3.30 (1H,m), 4.47 (1H, d, J=3 Hz), 7.73 (1H, d, J=6 Hz), 7.90 (2H, d, J=8.5 Hz),8.01 (2H, d, J=8.5 Hz), 9.19 (2H, s) and 9.21 (1H, s). LCMS: (MH)⁺=334.

Synthesis 74N-(4-(2′,4′-Difluorobiphenyl-4-ylsulfonamido)cyclohexyl)-2,2,2-trifluoroacetamide(ABD864a)

A solution of ABD787 (410 mg, 1.12 mmol) in dry THF (10 ml) was stirredat room temperature and triethylamine (350 μL, 250 mg, 2.5 mmol) andTFAA (200 μL, 300 mg, 1.44 mmol) were added, causing the solution toturn deep red and get warm. The mixture was stirred at room temperaturefor 3 hours and then poured into water (10 mL) and EtOAc (20 mL) and thelayers were separated. The organic phase was washed with water (10 mL)and sat. NaHCO₃(aq., 10 mL) and dried over MgSO₄. After evaporation ofthe solvents, the crude product was purified by column chromatography onSiO₂ (1:1 acetone/hexane) to give the title compound as a waxy orangesolid (370 mg, 71%).

Synthesis 752′,4′-Difluoro-N-(cis-4-(2,2,2-trifluoroethylamino)cyclohexyl)biphenyl-4-sulfonamide(ABD864)

A solution ofN-(4-(2′,4′-difluorobiphenyl-4-ylsulfonamido)cyclohexyl)-2,2,2-trifluoroacetamide(350 mg, 0.76 mmol) in THF (20 mL) was stirred under argon at roomtemperature and BH₃/THF (1 M, 3.8 mL) was added. The mixture was heatedto 50° C. and stirred for 4 hours, after which LCMS analysis indicatedthe reaction to be proceeding, but significant starting material waspresent. Further BH₃/THF (1 M, 2.5 mL) was added and the mixture washeated at 50° C. overnight. The mixture was then cooled and NH₄Cl (sat.aq., 10 mL) was added cautiously, followed by water to dissolve all thesolids. The mixture was then extracted with EtOAc (3×20 mL) and thecombined extracts were dried over MgSO₄. After evaporation of thesolvents, the crude material was purified by column chromatography onSiO₂ (30% acetone/hexane) affording a viscous pale yellow oil (270 mg,79%), which LCMS indicated to be only 78% pure and a mixture ofdiastereomers.

The mixture of diastereomers was dissolved in HPLC grade MeOH (5 mL) andpurified by reverse-phase preparative HPLC, eluting with 50%-80%acetonitrile/water containing 0.1% NH₄OH (aq.), to give baselineseparation of the two peaks. The fractions corresponding to the firstpeak were combined and the acetonitrile was removed under reducedpressure. The residue was extracted with DCM (30 mL, 2×15 mL) and thecombined extracts were dried over MgSO₄. Evaporation of the solventsgave the title cis-isomer as a pale yellow solid (66 mg, 24%). ¹H NMR(300 MHz, CDCl₃): δ 1.07-1.30 (5H, m), 1.86-1.95 (4H, m), 2.46-2.54 (1H,m), 3.17 (2H, q, J=9.5 Hz), 3.22-3.11 (1H, m), 4.49 (1H, d, J=7.5 Hz),6.91-7.03 (2H, m), 7.43 (1H, td, J=8.5 Hz, 6 Hz), 7.64 (2H, dd, J=8.5Hz, 1.5 Hz) and 7.93 (2H, d, J=8.5 Hz). LCMS: (MH)⁺=449.

Synthesis 762′,4′-Difluoro-N-(trans-4-(2,2,2-trifluoroethylamino)cyclohexyl)biphenyl-4-sulfonamide(ABD865)

Continuing from the separation as described for ABD864: the fractionscorresponding to the second peak were combined and the acetonitrile wasremoved under reduced pressure, the residue was extracted with DCM (30mL, 2×15 mL) and the combined extracts were dried over MgSO₄.Evaporation of the solvents gave the title trans-isomer as a pale yellowsolid (48 mg, 24%). ¹H NMR (300 MHz, CDCl₃): δ 1.39-1.71 (8H, m), 2.68(1H, br s), 3.13 (2H, q, J=9.5 Hz), 3.38 (1H, br s), 4.92 (1H, d, J=7Hz), 6.90-7.04 (2H, m), 7.43 (1H, td, J=8.5 Hz, 6.5 Hz), 7.63 (2H, dd,J=8.5 Hz, 2 Hz) and 7.95 (2H, d, J=8.5 Hz). LCMS: (MH)⁺=449.

Synthesis 77 tert-Butyl-4-hydroxycyclohexylcarbamate

trans-4-Aminocyclohexanol hydrochloride (13.5 g) was suspended in dryDCM (100 mL) and cooled to 5-10° C. To this, BOC anhydride (24.6 mL,23.32 g, 106.8 mmol) was added drop-wise over 15 minutes. The reactionmixture was stirred under nitrogen for 15 minutes. Triethylamine (37.2mL) was added and the mixture was stirred overnight, allowing thetemperature to rise to room temperature. The solution was diluted withwater (100 mL) and extracted with DCM (2×50 mL), organic layer driedover Na₂SO₄. Evaporation of the solvents gave the title compound as acolorless solid (17.1 g, quantitative).

Synthesis 78 tert-Butyl 4-oxocyclohexylcarbamate

tert-Butyl-4-hydroxycyclohexylcarbamate (17 g) and Celite (17 g) weresuspended in dry DCM (100 mL). PCC (25.5 g) was added portion-wisewithin 10-15 minutes. The reaction was stirred under nitrogen for 2.5hours. The solvent was removed under reduced pressure and the residuewas re-dissolved in EtOAc/n-hexane (1000 mL) and filtered throughcelite. The organic layer was dried over Na₂SO₄. Evaporation of thesolvents gave the title compound as a colorless solid (16.1 g,quantitative).

Synthesis 79 tert-Butyl cis-4-hydroxy-4-methylcyclohexylcarbamate andtert-butyl trans-4-hydroxy-4-methylcyclohexylcarbamate

A solution of methylmagnesium chloride (3 M in THF, 71.4 mL) was addedto a solution of tert-butyl 4-oxocyclohexylcarbamate (16 g, 75.01 mmol)in THF at −75° C. The mixture was stirred overnight, allowing thetemperature to rise to room temperature. The reaction mixture wasquenched with saturated ammonium chloride solution and the volatilesolvent removed under reduced pressure. The residue was taken up inwater (50 mL) and DCM (100 mL) and solid citric acid were added untilthe layers separated. The organic phase was washed with brine and dried(Na₂SO₄). Evaporation of the solvents gave a crude sticky mass which waspurified by column chromatography and the trans isomer isolated as acolorless solid (660 mg) and the cis isomer as a colourless solid (1.0g).

Synthesis 80 trans-4-Amino-1-methyl-cyclohexanol andcis-4-amino-1-methyl-cyclohexanol

To the Boc-protected amines from Synthesis 79 was added ethanolic HCl(20 mL) at 0° C. The solution was allowed to warm to room temperatureand stirred for 2 hours. The reaction mixture was concentrated to givethe trans isomer as a light yellow oil (400 mg) and the cis isomer (800mg) as a light yellow oil.

Synthesis 814-Bromo-N-(cis-4-hydroxy-4-methylcyclohexyl)benzenesulfonamide (ABD899a)

A suspension of cis-4-amino-1-methyl cyclohexanol (0.6 g) and4-bromobenzenesulfonyl chloride (1.78 g) in chloroform (20 mL) wasstirred under nitrogen at 0° C. Triethylamine (3.2 mL) was added and themixture was stirred for 16 hours, allowing the temperature to rise toroom temperature. The solution was diluted with EtOAc (50 mL) and washedwith water (2×20 mL), 1 M HCl (20 mL) and brine (20 mL) and dried overNa₂SO₄. Evaporation of the solvents gave a light yellow solid, which wastriturated with n-pentane and ether to give the title compound as awhite solid (1.2 g, 75%).

Synthesis 822′,4′-Difluoro-N-(cis-4-hydroxy-4-methylcyclohexyl)biphenyl-4-sulfonamide(ABD899)

Using a method analogous to Method B, with ABD899a and2′,4′-difluorophenylboronic acid, the title compound was obtained as aclear oil. Trituration with n-pentane and ether gave a white solid. ¹HNMR (300 MHz, CDCl₃): δ 1.23 (1H, s), 1.25 (3H, s), 1.44-1.51 (4H, m),1.65 (2H, m), 1.85 (2H, m), 3.35 (1H, m), 4.59 (1H, d, J=6.6 Hz),6.91-7.03 (2H, m), 7.44 (1H, m), 7.63 (2H, dd, J=8.5 Hz, 2 Hz) and 7.94(2H, dd, J=8.7 Hz). MS, m/z: Calcd, 381.12; Found, 380.4 (M).

Synthesis 832′,4′-Difluoro-N-(trans-4-hydroxy-4-methylcyclohexyl)biphenyl-4-sulfonamide(ABD900)

A suspension of trans-4-amino-1-methyl-cyclohexanol (0.3 g) and2′,4′-difluorobiphenylsulfonyl chloride (0.8 g) in chloroform (20 mL)were stirred under nitrogen at 0° C. Triethylamine (1.60 mL) was addedand the mixture was stirred for 16 hours, allowing the temperature torise to room temperature. The solution was diluted with EtOAc (50 mL)and washed with water (2×20 mL), 1 M HCl (20 mL) and brine (20 mL) anddried over Na₂SO₄. Evaporation of the solvents gave a dark brown solidwhich was purified by column chromatography followed by trituration withn-pentane and ether to give the title compound as a buff sticky solid(80 mg, 10% yield). Melting point: 105°-107° C. MS, m/z: Calcd, 381.12;Found, 380.5 (M). ¹H NMR (300 MHz, CDCl₃): δ 0.98 (1H, s), 1.20 (3H, s),1.40 (2H, m), 1.60 (5H, m), 3.18 (1H, m), 4.38 (1H, d, J=7.8 Hz),6.91-7.03 (2H, m), 7.44 (1H, m), 7.63 (2H, dd, J=8.5 Hz, 2 Hz) and 7.94(2H, dd, J=8.7 Hz). MS, m/z: Calcd, 381.12; Found, 380.5 (M).

Biological Methods

Initial screening of candidate compounds was performed using in vitroassays to determine potency, metabolic stability and solubility inbiologically relevant fluids. Potency was assessed using a viabilityassay based on the survival of the J774 macrophage cell line.Macrophages are closely related to osteoclasts and have been usedpreviously as a model system for osteoclast survival (see, e.g., Luckmanet al., 1998). Like osteoclasts, J774 macrophages are dependent oncontinued NFκB activation for survival, thereby providing a valuablescreen for compounds with anti-inflammatory activity. Metabolicstability was measured by determining the rate of disappearance ofcompound in the presence of human liver microsomal preparations, asquantified by LC-MS/MS. Solubility was measured by equilibration of thecompound in fasted state simulated intestinal fluid (FaSSIF) andquantified by HPLC.

Alamar Blue Macrophage J774 Viability Assay

In vitro potency as anti-inflammatory agents was determined for a numberof APSAC compounds by incubation with J774 macrophages and subsequentdetermination of cell viability.

J774 cells were plated at 10⁴ cells per well in 100 μL αMEM (α ModifiedEagle Medium) in 96-well plates and grown overnight. The next day, testcompounds were added to the cultures, and cultures were continued foranother 72 hours. At the end of the culture period, cell survival wasdetermined using an Alamar Blue assay as previously described (see,e.g., Nociari et al., 1998).

Alamar Blue is an oxidation-reduction sensitive indicator. The dyeitself is in the oxidised state, which is blue and non-fluorescent. Thedye can accept electrons from reducing species, such as NADPH and FADH,to form a reduced dye species, which is red and fluorescent. Thus thetransformation from oxidised form to reduced form can be measured byfluorimetric or colourimetric means. For fluorescence measurements,530-560 nm excitation and 590 nm emission wavelengths are typicallyused. For colourimetric measurements, absorbance at 570 nm (reducedform) and 600 nm (oxidised form) is typically measured. A simplecalculation is performed to determine the relative quantities of the twospecies.

A high ratio of the reducing species, NADPH and FADH, to thecorresponding oxidised species, NADP and FAD, is an indicator that cellsare proliferating and viable. A low ratio indicates cells that arequiescent or non-viable.

Briefly, Alamar Blue (Biosource International) was added undiluted tothe each well (1:10 v/v, 10 μL). The plate was incubated at 37° C. for3-4 hours and the fluorescence was measured at 590 nm, with a 25 nmbandwidth. A high reading indicated cells with normal viability, and alow reading indicated cells that have been damaged and are no longerproliferating normally. The controls gave a high fluorescence reading,indicating a high number of live, healthy cells. A potent test compoundgave a low fluorescence reading. The average results for each testcompound (n=5) were expressed as a percent (%) of the average controlvalue.

Addition of Compounds. All of the compounds studied were made up as 100mM solutions in DMSO. These stock solutions were then diluted1000-10000× in culture medium (αMEM). From these 100 μM or 10 μMsolutions, convenient quantities (3-33 μL) were added directly to thewells so as to give the desired final compound concentration.

This assay offers numerous advantages over other assays, including MTTassays: it permits a higher throughput; it is more sensitive; it isnon-damaging to the cells; it is faster; and it generally gives anidentical result to MTT assays.

Aqueous Solubility Measurements

Thermodynamic aqueous solubility was measured by equilibration of anumber of APSAC compounds, in the solid state, with fasted statesimulated intestinal fluid (FaSSIF) and quantified by HPLC. Measurementof solubility in FaSSIF provides a valuable model for the prediction ofdrug dissolution following oral administration.

FaSSIF was prepared as described below:

Preparation of blank FaSSIF: NaOH pellets (174 mg), NaH₂PO₄.2H₂O (2.235g), and NaCl (3.093 g) were dissolved in 500 mL of water. The pH wasadjusted to 6.5 using 1 M NaOH solution.

Preparation of FaSSIF: Sodium taurocholate (165 mg) was dissolved in 25mL blank FaSSIF. 0.6 mL of a solution containing 100 mg/mL lecithin inmethylene chloride was added. The methylene chloride was eliminatedunder vacuum at about 40° C. The vacuum was drawn for 15 minutes at 250mbar, followed by 15 minutes at 100 mbar. This resulted in a clear,micellar solution, having no perceptible odour of methylene chloride.After cooling to room temperature, the solution was then adjusted to 100mL with blank FaSSIF.

Aqueous solubility was determined by suspending separately sufficientcompound in FaSSIF to give a maximum final concentration of ≧10 mg/mL ofthe parent free-form of the compound. The suspension was equilibrated at25° C. for 24 hours, and then the pH was measured. The suspension wasthen filtered through a glass fibre C filter into a 96-well plate. Thefiltrate was then diluted by a factor of 100. Quantification was made byHPLC with reference to a standard solution of compound at approximately0.1 mg/mL in DMSO. Different volumes of the standard, diluted andundiluted sample solutions were injected. The solubility was calculatedusing the peak areas determined by integration of the peak found at thesame retention time as the principal peak in the standard injection.Detection conditions are shown in the table below. Analysis wasperformed on an Agilent HP1100 series system equipped with a diode arraydetector and using ChemStation software vB.02.01-SR1.

TABLE 1 HPLC Method Parameters for Solubility Measurements Type ofmethod: Reverse phase with gradient elution Column: Phenomenex Luna, C18(2) 5 μm 50 × 4.6 mm Column 25 Temperature (° C.): Standard Injections(μL): 1, 2, 3, 5, 7, 10 Test Injections (μL): 1, 2, 3, 10, 20, 50Detection: Wavelength, 260, 80 Bandwidth (nm): Flow Rate (mL/min): 2Phase A: 0.1% TFA in water Phase B: 0.085% TFA in acetonitrileTimetable: Time (min) % Phase A % Phase B 0.0 95 5 1.0 80 20 2.3 5 953.3 5 95 3.5 95 5 4.4 95 5Human Liver Microsomal Stability Assay

Metabolic stability of APSAC derivatives was measured by determinationof the rate of compound disappearance when incubated in the presence ofhuman liver microsomes. Liver microsomes are prepared from theendoplasmic reticulum of hepatocytes and are the primary source of themost important enzymes (cytochrome P450) involved in drug metabolism.Study of drug stability in the presence of liver microsomes is acceptedas a valuable model permitting rapid prediction of in vivo drugstability.

Protocol Summary:

Human liver microsomes were obtained from a commercial source. Testcompounds (3 μM) were incubated with pooled liver microsomes (male andfemale). Samples were incubated for a 45 minute period and removed at 5time points and test compounds were analysed by LC-MS/MS.

Microsomes (final protein concentration 0.5 mg/mL), 0.1 M phosphatebuffer pH 7.4, and test compound (final concentration 3 μM; diluted from10 mM stock solution to give a final DMSO concentration of 0.25%) wereincubated at 37° C. prior to the addition of NADPH (final concentration1 mM) to initiate the reaction. The final incubation volume was 25 μL. Acontrol incubation was included for each compound tested, where 0.1 Mphosphate buffer pH 7.4 was added instead of NADPH. The controlcompounds testosterone and 7-hydroxycoumarin were included in eachexperiment and all incubations were performed singularly for eachcompound.

Each compound was incubated for 0, 5, 15, 30, and 45 minutes. Thecontrol (minus NADPH) was incubated for 45 minutes only. The reactionswere stopped by the addition of 50 μL methanol containing internalstandard at the appropriate time points. The incubation plates werecentrifuged at 2500 rpm for 20 minutes at 4° C. to precipitate theprotein.

Quantitative Analysis:

Following protein precipitation, the sample supernatants were combinedin cassettes of up to 4 compounds and analysed using standard LC-MS/MSconditions.

Data Analysis:

From a plot of the natural logarithm of the peak area ratio (i.e., theratio of compound peak area:internal standard peak area) against time,the gradient of the line was determined. Subsequently, half-life andintrinsic clearance were calculated using the equations below:Eliminated rate constant (k)=(−gradient).Half life (t _(1/2)) (min)=0.063/k.Intrinsic Clearance (CL _(int)) (μL/min/million cells)=(V×0.693)/t_(1/2).wherein V=Incubation volume (μL/mg microsomal protein).Pharmacokinetics Studies

Absorption and metabolic stability were studied using an in vivopharmacokinetics assay. Drug levels were assessed usingultra-performance LC/TOF-MS.

Three male Sprague-Dawley rats, 200-300 g, were dosed per route. Testcompound was administered either orally or intravenously (dose level of1 mg/kg body weight). Test compound was formulated in 50:50tetraethylene glycol:PBS for both routes. Animals were given free accessto food throughout the study. On the day prior to dosing, the carotidartery was cannulated for sample collection and for the intravenousstudy the jugular vein was cannulated to enable dosing.

Blood samples were taken from the carotid artery at the following timepoints and placed in heparinised tubes:

Oral dosing—predose, 0.25, 0.5, 1, 2, 4, 8 and 24 hours post dose.

IV dosing—predose, 0.08, 0.25, 0.5, 1, 2, 4 and 8 hours post dose.

After the final time point, the animals were sacrificed by an overdoseof anaesthetic.

Blood samples were centrifuged to obtain plasma, which was transferredto a separate container and frozen at −20° C.

Sample Preparation:

Samples were thawed at room temperature and prepared by proteinprecipitation with acetonitrile in the ratio 1:2 with plasma, followedby centrifugation for 10 minutes at 16,100×g (Eppendorf 5415D, EppendorfAG, Hamburg, Germany). The supernatants were collected for analysis. Thestandard samples were prepared similarly, after spiking blank rat plasmasamples to study compound concentrations at 1, 2, 5, 10, 20, 50, 100,200, 500 and 1000 ng/mL. In addition, extra samples were prepared from0-1 hour i.v. samples by diluting 1/20 with 50% aqueous acetonitrile toavoid exceeding the linear range of the analytical method.

Analytical Methods:

A Waters Acquity liquid ultra-performance chromatographic system (WatersCorp., Milford, Mass., USA) with autosampler, vacuum degasser and columnoven was used. The analytical column used for all compounds was a WatersBEH C18, (2.1×50 mm, 1.7 μm, Waters Corp, Milford, Mass., USA) togetherwith a 0.2 μm on-line filter before the column. The eluents were 0.1%acetic acid (A, pH 3.2) and methanol (B). Gradient elution from 5% to60% B in two minutes was employed, followed by one minute gradient to90% B and column equilibration. The flow rate was 0.5 mL/min and thecolumn oven temperature was 35° C. The flow was directed to the MS viaWater Acquity photo-diode-array (PDA) detector. LC/TOF-MS data wererecorded with a Micromass LCT Premier XE time-of-flight (TOF) massspectrometer (Micromass Ltd., Manchester, England) equipped with aLockSpray electrospray ionization source. A positive ionization mode ofelectrospray was used for all compounds. The mass range of m/z 100-900was acquired. The W-option of the reflector was used, and the DRE(dynamic range enhancement) option was set to on. The mass spectrometerand HPLC system were operated under Micromass MassLynx 4.1 software.Leucine enkephalin ([M+H]⁺ m/z 556.2771) was used as a lock masscompound for accurate mass measurements and was delivered into theLockSpray probe with a syringe pump. Masslynx 4.1 software was used forcontrolling the instrumentation and for data processing.

Calculations:

The pharmacokinetic parameters for the test compounds were calculated byWinNonlin Pro (Pharsight Corp, CA) using standard noncompartmentalmethods. The elimination phase half-life (t_(1/2)) was calculated byleast-squares regression analysis of the terminal linear part of the logconcentration-time curve. The area under the plasma concentration-timecurve (AUC) was determined by use of the linear trapezoidal rule up tothe last measurable concentration and thereafter by extrapolation of theterminal elimination phase to infinity. The tentative oralbioavailability (F) was calculated by dividing the AUC (0-24 hours)after p.o. administration by the AUC (0-8 hours) after i.v.administration, i.e., F=AUC(p.o.)/AUC(i.v), and reported as percentages(%).

Caspase Induction Study

The ability to activate caspase 3 was studied using a fluorogenic enzymesubstrate assay.

Briefly, human primary monocytes were isolated from whole blood usingFicoll gradients. The resulting cells were plated into microwell platesfor 24 hours after which non-adherent cells were removed by washing.Cells were differentiated in the presence of 100 ng/mL MCSF. Cells werepre-treated with 10 μM test compound for 1 hour prior to stimulationwith 10 ng/mL TNFα. Caspase 3 activation as an indicator of apoptosiswas detected using the Nucview488 stain, which was added one hour priorto visualisation. The Nucview488 stain indicates the activation ofcaspase 3 (CPP32, apopain, YAMA), a cysteine peptidase which plays a keyrole in the induction of apoptosis in individual whole mammalian cells.Essentially, Nucview488 consists of a fluorogenic DNA dye and a DEVDsubstrate moiety specific for caspase 3. In itself, Nucview488 isnonfluorescent. However, upon entering the cell cytoplasm, Nucview488 iscleaved by caspase 3 to form a high-affinity DNA dye. The released DNAdye migrates to the cell nucleus to stain the nucleus bright green. Thisfluorescent staining produced in response to caspase 3 activity ismonitored using fluorescent light microscopy.

Biological Data Biological Study 1

The biological activity of a number of APSAC compounds was determinedand compared with the biological activity of a range of structurallyrelated compounds using the assays described previously.

IC₅₀ values were determined for several APSAC compounds, as well asseveral reference compounds, using the Alamar Blue macrophage J774viability assay described above. The results are summarized in thefollowing tables.

TABLE 2A Alamar Blue Macrophage J774 Viability Assay Data (ReferenceCompounds)

Compound —R^(X2) —R^(X4) —Q^(Ref) IC₅₀ (μM) ABD455 —Cl —Cl

0.50 ABD456 —F —F

0.25 ABD466 —F —F

3.0 ABD575 —F —Cl

0.40

TABLE 2B Alamar Blue Macrophage J774 Viability Assay Data

Compound —R^(X2) —R^(X4) —DQ IC₅₀ (μM) ABD599 —F —F

0.07 ABD777 —F —F

1.9 ABD769 —F —F

4.59 ABD770 —F —F

— ABD771 —F —F

— ABD772 —F —F

— ABD773 —F —F

0.13 ABD774 —F —F

— ABD775 —F —F

— ABD796 —F —F

<0.3 ABD813 —F —F

0.57 ABD815 —F —F

<0.3 ABD776 —F —F

0.8 ABD781 —F —F

0.3 ABD786 —F —F

0.28 ABD787 —F —F

3.55 ABD794 —F —F

2.1 ABD795 —F —F

2.7 ABD798 —F —F

0.6 ABD799 —F —F

0.4 ABD812 —F —F

7.6 ABD816 —F —F

0.8 ABD817 —F —F

<1 ABD819 —F —F

2.4 ABD820 —F —F

2.5 ABD821 —F —F

>10 ABD822 —F —F

6.98 ABD824 —F —F

7.2 ABD826 —F —F

1.0 ABD864 —F —F

>10 ABD865 —F —F

5.9

TABLE 2C Alamar Blue Macrophage J774 Viability Assay Data

Compound —Ar IC₅₀ (μM) ABD599

0.07 ABD655

0.18 ABD665

4.9 ABD705

0.83 ABD710

1.98 ABD712

5.46 ABD732

4.32 ABD735

0.09 ABD742

0.77 ABD756

2.18 ABD836

0.28 ABD837

8.88 ABD861

Inactive

These data demonstrate that it is possible to replace the phenylenegroup of -Q^(Ref) with a saturated carbocyclic structure without a lossof potency. These data also demonstrate that it is possible to make arange of substitutions on the biaryl system and retain potency. The dataalso demonstrate that these replacements and substitutions are neithertrivial nor predictable and can lead either to an increase or a decreasein potency.

Biological Study 2

The metabolic stability of a number of APSAC compounds was determinedand compared with the metabolic stability of a range of structurallyrelated compounds using the assays described previously.

Biological half-life values (t_(1/2)) were determined for several APSACcompounds, as well as several reference compounds, using the human livermicrosomal stability assay described above. The results are summarizedin the following tables.

TABLE 3A Human Liver Microsomal Stability Data (Reference Compounds)

Compound —R^(X2) —R^(X4) —Q^(Ref) T_(1/2) (min) ABD455 —Cl —Cl

28 ABD456 —F —F

30 ABD466 —F —F

2 ABD575 —F —Cl

42

TABLE 3B Human Liver Microsomal Stability Data

Compound —R^(X2) —R^(X4) —DQ T_(1/2) (min) ABD599 —F —F

287 ABD655 —F —Cl

228 ABD777 —F —F

69 ABD769 —F —F

42 ABD770 —F —F

— ABD771 —F —F

— ABD772 —F —F

— ABD773 —F —F

54 ABD774 —F —F

— ABD775 —F —F

— ABD796 —F —F

54 ABD813 —F —F

45.4 ABD815 —F —F

13.2 ABD776 —F —F

137 ABD781 —F —F

41 ABD786 —F —F

12 ABD787 —F —F

Stable ABD794 —F —F

Stable ABD795 —F —F

15 ABD798 —F —F

Stable ABD799 —F —F

Stable ABD812 —F —F

585

These data demonstrate that it is possible to replace the phenylenegroup of -Q^(Ref) with a saturated carbocyclic structure without a lossof metabolic stability. The data also demonstrate that this replacementis neither trivial nor predictable and can lead either to an increase ora decrease in metabolic stability.

Biological Study 3

The solubility of a number of APSAC compounds was determined andcompared with the solubility of a range of structurally relatedcompounds using the assays described previously.

Solubility in the biological model fasted state simulated intestinalfluid (FaSSIF) was determined for several APSAC compounds, as well asseveral reference compounds, using the aqueous solubility assaydescribed above. The results are summarized in the following tables.

TABLE 4A Aqueous Solubility Data (Reference Compounds)

Solubility Compound R^(X2) R^(X4) Q^(Ref) (mg/mL) ABD455 Cl Cl

0.02 ABD456 F F

0.04 ABD466 F F

0.04 ABD575 F Cl

0.07

TABLE 4B Aqueous Solubility Data

Solubility Compound —R^(X2) —R^(X4) DQ (mg/mL) ABD599 —F —F

0.03 ABD655 —F —Cl

0.03 ABD777 —F —F

0.06 ABD769 —F —F

0.07 ABD770 —F —F

— ABD771 —F —F

— ABD772 —F —F

— ABD773 —F —F

0.89 ABD774 —F —F

— ABD775 —F —F

— ABD796 —F —F

0.20 ABD813 —F —F

0.33 ABD815 —F —F

0.25 ABD776 —F —F

0.082 ABD781 —F —F

0.59 ABD786 —F —F

0.032 ABD787 —F —F

0.14 ABD794 —F —F

0.012 ABD795 —F —F

0.05 ABD798 —F —F

4.7 ABD799 —F —F

7.2 ABD812 —F —F

0.98

These data demonstrate that it is possible to achieve a substantialincrease in solubility by replacing the phenylene group of -Q^(Ref) witha saturated carbocyclic structure. The data also demonstrate that thisreplacement is neither trivial nor predictable and can lead either to anincrease or a decrease in metabolic stability. Furthermore, the datashow the exceptional aqueous solubility imparted by the groups3-(CH₂OH)-cyclopent-1-yl (e.g., as found in ABD773),4-(CH₂OH)-cyclohex-1-yl (e.g., as found in ABD781) and4-(NMe₂)-cyclohexan-1-yl (e.g., as found in ABD798 and ABD799).

Biological Study 4

The oral absorption of the APSAC compounds, ABD773 and ABD781, wasdetermined in a rat model as described previously.

Plasma levels of ABD773 or ABD781, following oral or intravenous dosage(1 mg/kg) (see FIGS. 1 and 2 and FIGS. 3 and 4 respectively), wereinvestigated in vivo in rats using an ultra-performance LC/TOF-MSdetection system, as described previously. The pharmacokinetic data aresummarized in the following table.

TABLE 4 Pharmacokinetic data ABD773 ABD781 Reference Compound ABD455 (1mg/kg) (1 mg/kg) (2.5 mg/kg) Bioavailability F % 13 43 3 p.o. i.v. p.o.i.v. p.o. i.v. AUC (ng/mL/min) 1500 11900 9600 22400 1.2 9 T½ (h) 3.170.81 3.28 0.87 0.8 0.53

The data show improved absorbance of the APSAC compound, ABD773, abovethat of the reference compound ABD455 (see FIGS. 5 and 6; Table 4) witha bioavailability (F) of 13% and an extended half life of 3.17 hours.The APSAC compound, ABD781, is especially well absorbed following oraladministration with a bioavailability (F) of 43% and an extended halflife of 3.28 hours and is superior to the reference compound ABD455. Thedata demonstrate that the APSAC compound ABD781 shows the propertiesrequired for an orally active drug.

Biological Study 5

The ability of APSAC compounds to activate caspase 3 in the presence ofTNFα was determined using the fluorogenic enzyme substrate assaydescribed previously.

FIG. 7 shows a series of images of human monocytes monitored usingfluorescent light microscopy and showing the effects of ABD599 andABD781 on caspase 3 activation in the presence of TNFα: (a) TNFα alone;(b) TNFα with 10 μM ABD599, and (c) TNFα with 10 μM ABD781, by the useof a dye which fluoresces only on activation by caspase 3.

These data show that in the presence of TNFα alone no fluorescence isdetected (the image is plain black with no light emission from thecells, as would be shown by white spots). This indicates that there islittle activation of caspase 3 and that the cells do not undergo activeapoptosis upon treatment with TNFα alone. Upon the addition of eitherABD599 or ABD781, fluorescence is detected in the cell population, asdemonstrated by the images showing a black background with multiplelight emitting cells which appear as white dots. These data indicatethat there has been significant activation of caspase 3 and that thecells are undergoing active apoptosis.

These data demonstrates that the APSAC compounds are able to activatecaspase 3, and thus induce apoptosis, and therefore may be useful in thetreatment of tumours associated with inactivation or impairment ofcaspase induction or with aberrant caspase signalling.

The foregoing has described the principles, preferred embodiments, andmodes of operation of the present invention. However, the inventionshould not be construed as limited to the particular embodimentsdiscussed. Instead, the above-described embodiments should be regardedas illustrative rather than restrictive, and it should be appreciatedthat variations may be made in those embodiments by workers skilled inthe art without departing from the scope of the present invention.

REFERENCES

A number of patents and publications are cited herein in order to morefully describe and disclose the invention and the state of the art towhich the invention pertains. Full citations for these references areprovided below. Each of these references is incorporated herein byreference in its entirety into the present disclosure, to the sameextent as if each individual reference was specifically and individuallyindicated to be incorporated by reference.

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The invention claimed is:
 1. A compound selected from compounds of thefollowing formula, and pharmaceutically acceptable salts thereof:

wherein: -A is:

—Ar is independently phenyl, pyridinyl, or pyrimidinyl; p isindependently an integer from 0 to 3; q is independently an integer from0 to 3; —R^(SN) is independently —H or saturated aliphatic C₁₋₄alkyl;-DQ is independently -D¹-Q¹ or -D²=O; -D¹- is independentlycyclopentane-di-yl, cyclohexane-di-yl, cycloheptane-di-yl,bicyclo[3.1.1]heptane-di-yl, or bicyclo[3.2.1]octane-di-yl, and isoptionally substituted with one or more groups —R^(D); -D²= isindependently cyclopentane-yl-ylidene, cyclohexane-yl-ylidene,cycloheptane-yl-ylidene, bicyclo[3.1.1]heptane-yl-ylidene, orbicyclo[3.2.1]octane-yl-ylidene, and is optionally substituted with oneor more groups —R^(D); each —R^(D) is independently —F, —Cl, —Br, —I,—R^(DD), —CF₃, —OH, —OR^(DD), —NH₂, —NHR^(DD), or —NR^(DD) ₂; each—R^(DD) is saturated aliphatic C₁₋₄alkyl; -Q¹ is independently:

either: each —R^(1N) is independently —H, —R^(CN), or —R^(CF); each—R^(2N) is independently —H, —R^(CN), or —R^(CF); each —R^(CN) issaturated aliphatic C₁₋₄alkyl; and each —R^(CF) is saturated aliphaticC₁₋₄fluoroalkyl; or: each —NR^(1N)R^(2N) is independently azetidino,pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperazino,morpholino, thiomorpholino, azepino, or diazepino, each optionallysubstituted with one or more groups selected from saturated aliphaticC₁₋₄alkyl; —R^(1A) is independently —H, —R^(C), or —R^(F); and —R^(2A)is independently —H, —R^(C), or —R^(F); or —R^(1A) and —R^(2A) togetherform a saturated aliphatic C₂₋₄alkylene group; —R^(1B) is independently—H, —R^(C), or —R^(F); and —R^(2B) is independently —H, —R^(C), or—R^(F); or —R^(1B) and —R^(2B) together form a saturated aliphaticC₂₋₄alkylene group; or —R^(1B) and —R^(2B) together form ═O; —R^(3A) isindependently —H, —R^(C), or —R^(F); and —R^(4A) is independently —H,—R^(C), or —R^(F); or —R^(3A) and —R^(4A) together form a saturatedaliphatic C₂₋₄alkylene group; —R^(5A) is independently —H, —R^(C),—R^(F), or —R^(J); and —R^(6A) is independently —H, —R^(C), or —R^(F);or —R^(5A) and —R^(6A) together form a saturated aliphatic C₂₋₄alkylenegroup; —R^(3B) is independently —H, —R^(C), or —R^(F); and —R^(4B) isindependently —H, —R^(C), or —R^(F); or —R^(3B) and —R^(4B) togetherform a saturated aliphatic C₂₋₄alkylene group; —R^(5B) is independently—H, —R^(C), —R^(F), —OH, or —OR^(O); and —R^(6B) is independently —H,—R^(C), or —R^(F); or —R^(5B) and —R^(6B) together form a saturatedaliphatic C₂₋₄alkylene group; each —R^(C) is saturated aliphaticC₁₋₄alkyl; each —R^(F) is saturated aliphatic C₁₋₄fluoroalkyl; —R^(O) issaturated aliphatic C₁₋₄alkyl; —R^(J) is independently —NH₂, —NHR^(JN1),—NR^(JN1) ₂, or —NR^(JN2)R^(JN3); each —R^(JN1) is saturated aliphaticC₁₋₄alkyl; —NR^(JN2)R^(JN3) is independently azetidino, pyrrolidino,imidazolidino, pyrazolidino, piperidino, piperazino, morpholino,thiomorpholino, azepino, or diazepino, each optionally substituted withone or more groups selected from saturated aliphatic C₁₋₄alkyl; each—R^(X) is independently —F, —Cl, —Br, —I, —R^(XX), —OH, —OR^(XX), —SH,—SR^(XX), —CF₃, —OCF₃, —SCF₃, —NH₂, —NHR^(XX), —NR^(XX) ₂,—NR^(YY)R^(ZZ), —C(═O)R^(XX), —OC(═O)R^(XX), —C(═O)OH, —C(═O)OR^(XX),—C(═O)NH₂, —C(═O)NHR^(XX), —C(═O)NR^(XX) ₂, —C(═O)NR^(YY)R^(ZZ),—OC(═O)NH₂, —OC(═O)NHR^(XX), —OC(═O)NR^(XX) ₂, —OC(═O)NR^(YY)R^(ZZ),—NHC(═O)R^(XX), —NR^(XX)C(═O)R^(XX), —NHC(═O)OR^(XX),—NR^(XX)C(═O)OR^(XX), —NHC(═O)NH₂, —NHC(═O)NHR^(XX), —NHC(═O)NR^(XX) ₂,—NHC(═O)NR^(YY)R^(ZZ), NR^(XX)C(═O)NH₂, —NR^(XX)C(═O)NHR^(XX),—NR^(XX)C(═O)NR^(XX) ₂, —NR^(XX)C(═O)NR^(YY)R^(ZZ), —CN, —NO₂,—S(═O)₂NH₂, —S(═O)₂NHR^(XX), —S(═O)₂NR^(XX) ₂, —S(═O)₂NR^(YY)R^(ZZ),—S(═O)R^(XX), —S(═O)₂R^(XX), —OS(═O)₂R^(XX), —S(═O)₂OH, or—S(═O)₂OR^(XX); and each —R^(XX) is independently saturated aliphaticC₁₋₆alkyl, phenyl, or benzyl, wherein said phenyl and benzyl areoptionally substituted with one or more groups selected from: —F, —Cl,—Br, —I, —CF₃, —OCF₃, —R^(XXX), —OH, —OR^(XXX), or —SR^(XXX); whereineach —R^(XXX) is saturated aliphatic C₁₋₄alkyl; and each —NR^(YY)R^(ZZ)is independently azetidino, pyrrolidino, imidazolidino, pyrazolidino,piperidino, piperazino, morpholino, thiomorpholino, azepino, ordiazepino, each optionally substituted with one or more groups selectedfrom saturated aliphatic C₁₋₄alkyl.
 2. A compound according to claim 1,wherein -DQ is -D¹-Q¹.
 3. A compound according to claim 2, wherein -D¹-is independently cyclopentane-di-yl or cyclohexane-di-yl, and isoptionally substituted with one or more groups —R^(D); wherein each—R^(D) is —R^(DD); and each —R^(DD) is saturated aliphatic C₁₋₄alkyl. 4.A compound according to claim 2, wherein -D¹- is independentlycyclopentane-1,3-di-yl, cyclohexane-1,4-di-yl, or4-methyl-cyclohexane-1,4-di-yl.
 5. A compound according to claim 4,wherein -A is:

wherein: either: ═W— is —CH═ and —Y═ is —CH═; or: ═W— is —CH═ and —Y═ is—N═; —R^(X2) is independently —H or —R^(X2S); —R^(X4) is independently—H or —R^(X4S); —R^(X2S) is —R^(X); and —R^(X4S) is —R^(X).
 6. Acompound according to claim 4, wherein -A is:

wherein: —R^(X2) is independently —H or —R^(X2S); —R^(X4) isindependently —H or —R^(X4S); —R^(X2S) is —R^(X); and —R^(X4S) is—R^(X).
 7. A compound according to claim 4, wherein -A is:

wherein: —R^(X2) is —R^(X2S); —R^(X4) is —R^(X4S); —R^(X2S) is —R^(X);and —R^(X4S) is —R^(X).
 8. A compound according to claim 7, wherein:each —R^(X) is independently —F, —Cl, —Br, —I, —R^(XX), —OH, —OR^(XX),—SH, —SR^(XX), —CF₃, —OCF₃, —SCF₃, —NH₂, —NHR^(XX), —NR^(XX) ₂,—NR^(YY)R^(ZZ), —C(═O)R^(XX), —OC(═O)R^(XX), —C(═O)OH, —C(═O)OR^(XX),—C(═O)NH₂, —C(═O)NHR^(XX), —C(═O)NR^(XX) ₂, —C(═O)NR^(YY)R^(ZZ), —CN,—NO₂, —S(═O)₂NH₂, —S(═O)₂NHR^(XX), —S(═O)₂NR^(XX) ₂, or—S(═O)₂NR^(YY)R^(ZZ); each —NR^(YY)R^(ZZ) is independently pyrrolidino,piperidino, piperazino, or morpholino, each optionally substituted withone or more groups selected from saturated aliphatic C₁₋₄alkyl.
 9. Acompound according to claim 7, wherein: —R^(X2S) is independently —F,—Cl, —Br, —I, —R^(XA), —OR^(XA), —SR^(XA), —CF₃, or —OCF₃, wherein each—R^(XA) is saturated aliphatic C₁₋₄alkyl; and —R^(X4S) is independently—F, —Cl, —Br, —I, —R^(XA), —OR^(XA), —SR^(XA), —CF₃, or —OCF₃, whereineach —R^(XA) is saturated aliphatic C₁₋₄alkyl.
 10. A compound accordingto claim 7, wherein: —R^(X2S) is independently —F or —Cl; and —R^(X4S)is independently —F or —Cl.
 11. A compound according to claim 9, whereinthe leading phenylene group:

is:

wherein: —R^(XC1) is independently —H or —R^(XCC); and —R^(XC2) is —H;or: —R^(XC1) is —H; and —R^(XC2) is independently —H or —R^(XCC); or:—R^(XC1) is —H; and —R^(XC2) is —H; each —R^(XCC) is independently —F,—Cl, or —R^(XCCC); each —R^(XCCC) is independently -Me or -Et.
 12. Acompound according to claim 11, wherein -Q¹ is independently:

wherein: —R^(1A) is independently —H or —R^(C); —R^(2A) is independently—H or —R^(C); —R^(1B) is independently —H or —R^(C); —R^(2B) isindependently —H or —R^(C); each —R^(C) is saturated aliphaticC₁₋₄alkyl; either: each —R^(1N) is independently —H or —R^(CN); each—R^(2N) is independently —H or —R^(CN); each —R^(CN) is saturatedaliphatic C₁₋₄alkyl; or: each —NR^(1N)R^(2N) is independentlypyrrolidino, piperidino, piperazino, or morpholino, each optionallysubstituted with one or more groups selected from saturated aliphaticC₁₋₄alkyl.
 13. A compound according to claim 11, wherein -Q¹ isindependently:

wherein: —R^(1A) is independently —H or —R^(C); —R^(2A) is independently—H or —R^(C); each —R^(C) is saturated aliphatic C₁₋₄alkyl.
 14. Acompound according to claim 11, wherein -Q¹ is independently:

wherein: —R^(1A) is independently —H or —R^(C); —R^(2A) is independently—H or —R^(C); each —R^(C) is -Me.
 15. A compound according to claim 11,wherein -Q¹ is independently:


16. A compound according to claim 11, wherein -Q¹ is independently:

wherein: —R^(1B) is independently —H or —R^(C); —R^(2B) is independently—H or —R^(C); each —R^(C) is saturated aliphatic C₁₋₄alkyl; either: each—R^(1N) is independently —H or —R^(CN); each —R^(2N) is independently —Hor —R^(CN); each —R^(CN) is saturated aliphatic C₁₋₄alkyl; or: each—NR^(1N)R^(2N) is independently pyrrolidino, piperidino, piperazino, ormorpholino, each optionally substituted with one or more groups selectedfrom saturated aliphatic C₁₋₄alkyl.
 17. A compound according to claim11, wherein -Q¹ is independently:

wherein: —R^(1B) is independently —H; —R^(2B) is independently —H;either: each —R^(1N) is independently —H or —R^(CN); each —R^(2N) isindependently —H or —R^(CN); each —R^(CN) is saturated aliphaticC₁₋₄alkyl; or: each —NR^(1N)R^(2N) is independently pyrrolidino,piperidino, piperazino, or morpholino, each optionally substituted withone or more groups selected from saturated aliphatic C₁₋₄alkyl.
 18. Acompound according to claim 11, wherein -Q¹ is independently:

wherein: —R^(1N) is independently —H or —R^(CN); —R^(2N) isindependently —H or —R^(CN); and each —R^(CN) is saturated aliphaticC₁₋₄alkyl.
 19. A compound according to claim 12, wherein —R^(SN) is —H.20. A compound according to claim 1, wherein: -A is:

—R^(X2) is —R^(X2S); —R^(X4) is —R^(X4S); —R^(X2S) is —R^(X); —R^(X4S)is —R^(X); —R^(X2S) is independently —F or —Cl; —R^(X4S) isindependently —F or —Cl; the leading phenylene group:

is:

—R^(XC1) is independently —H or —R^(XCC); and —R^(XC2) is —H; or:—R^(XC1) is —H; and —R^(XC2) is independently —H or —R^(XCC); or:—R^(XC1) is —H; and —R^(XC2) is —H; each —R^(XCC) is independently —F,—Cl, or —R^(XCCC); each —R^(XCCC) is independently -Me or -Et; —R^(SN)is independently —H, -Me, or -Et; -DQ is -D¹-Q¹; -D¹- is independentlycyclopentane-1,3-di-yl, cyclohexane-1,4-di-yl, or4-methyl-cyclohexane-1,4-di-yl; -Q¹ is independently:

—R^(1A) is independently —H or —R^(C); —R^(2A) is independently —H or—R^(C); each —R^(C) is -Me.
 21. A compound according to claim 1,selected from the following compounds, and pharmaceutically acceptablesalts thereof:


22. A pharmaceutical composition comprising a compound according toclaim 1 and a pharmaceutically acceptable carrier, diluent, orexcipient.
 23. A compound according to claim 1, wherein: -A is:

either: ═W— is —CH═ and —Y═ is —CH═; or: ═W— is —CH═ and —Y═ is —N═;—R^(X2) is —R^(X2S); —R^(X4) is —R^(X4S); —R^(X2S) is —R^(X); and—R^(X4S) is R^(X); q is 0 or 1; each —R^(X) is independently —F, —Cl,—Br, —I, —R^(XX), —OH, —OR^(XX), —SR^(XX), —CF₃, —OCF₃, or —CN; each—R^(XX) is saturated aliphatic C₁₋₄alkyl; —R^(SN) is —H; -DQ is -D¹-Q¹;-D¹- is independently cyclohexane-1,4-di-yl or4-methyl-cyclohexane-1,4-di-yl; and -Q¹ is —OH.
 24. A compound accordingto claim 23, wherein ═W— is —CH═ and —Y═ is —CH═.
 25. A compoundaccording to claim 23, wherein ═W— is —CH═ and —Y═ is —N═.
 26. Acompound according to claim 23, wherein -D¹- is4-methyl-cyclohexane-1,4-di-yl.
 27. A compound according to claim 24,wherein -D¹- is 4-methyl-cyclohexane-1,4-di-yl.
 28. A compound accordingto claim 25, wherein -D¹- is 4-methyl-cyclohexane-1,4-di-yl.
 29. Acompound according to claim 23, wherein: either: —R^(X2S) is —F; and—R^(X4S) is —F; or: —R^(X2S) is —Cl; and —R^(X4S) is —Cl.
 30. A compoundaccording to claim 24, wherein: either: —R^(X2S) is —F; and —R^(X4S) is—F; or: —R^(X2S) is —Cl; and —R^(X4S) is —Cl.
 31. A compound accordingto claim 25, wherein: either: —R^(X2S) is —F; and —R^(X4S) is —F; or:—R^(X2S) is —Cl; and —R^(X4S) is —Cl.
 32. A compound according to claim26, wherein: either: —R^(X2S) is —F; and —R^(X4S) is —F; or: —R^(X2S) is—Cl; and —R^(X4S) is —Cl.
 33. A compound according to claim 27, wherein:either: —R^(X2S) is —F; and —R^(X4S) is —F; or: —R^(X2S) is —Cl; and—R^(X4S) is —Cl.
 34. A compound according to claim 28, wherein: either:—R^(X2S) is —F; and —R^(X4S) is —F; or: —R^(X2S) is —Cl; and —R^(X4S) is—Cl.
 35. A compound according to claim 23, wherein: the leadingphenylene group:

is:

—R^(XC1) is independently —H or —R^(XCC); —R^(XC2) is —H; —R^(XCC) isindependently —F, —Cl, or —R^(XCCC); and —R^(XCCC) is independently -Meor -Et.
 36. A compound according to claim 24, wherein: the leadingphenylene group:

is:

—R^(XC1) is independently —H or —R^(XCC); —R^(XC2) is —H; —R^(XCC) isindependently —F, —Cl, or —R^(XCCC); and —R^(XCCC) is independently -Meor -Et.
 37. A compound according to claim 25, wherein: the leadingphenylene group:

is:

—R^(XC1) is independently —H or —R^(XCC); —R^(XC2) is —H; —R^(XCC) isindependently —F, —Cl, or —R^(XCCC); and —R^(XCCC) is independently -Meor -Et.
 38. A compound according to claim 26, wherein: the leadingphenylene group:

is:

—R^(XC1) is independently —H or —R^(XCC); —R^(XC2) is —H; —R^(XCC) isindependently —F, —Cl, or —R^(XCCC); and —R^(XCCC) is independently -Meor -Et.
 39. A compound according to claim 27, wherein: the leadingphenylene group:

is:

—R^(XC1) is independently —H or —R^(XCC); —R^(XC2) is —H; —R^(XCC) isindependently —F, —Cl, or —R^(XCCC); and —R^(XCCC) is independently -Meor -Et.
 40. A compound according to claim 28, wherein: the leadingphenylene group:

is:

—R^(XC1) is independently —H or —R^(XCC); —R^(XC2) is —H; —R^(XCC) isindependently —F, —Cl, or —R^(XCCC); and —R^(XCCC) is independently -Meor -Et.
 41. A compound according to claim 29, wherein: the leadingphenylene group:

is:

—R^(XC1) is independently —H or —R^(XCC); —R^(XC2) is —H; —R^(XCC) isindependently —F, —Cl, or —R^(XCCC); and —R^(XCCC) is independently -Meor -Et.
 42. A compound according to claim 30, wherein: the leadingphenylene group:

is:

—R^(XC1) is independently —H or —R^(XCC); —R^(XC2) is —H; —R^(XCC) isindependently —F, —Cl, or —R^(XCCC); and —R^(XCCC) is independently -Meor -Et.
 43. A compound according to claim 31, wherein: the leadingphenylene group:

is:

—R^(XC1) is independently —H or —R^(XCC); —R^(XC2) is —H; —R^(XCC) isindependently —F, —Cl, or —R^(XCCC); and —R^(XCCC) is independently -Meor -Et.
 44. A compound according to claim 32, wherein: the leadingphenylene group:

is:

—R^(XC1) is independently —H or —R^(XCC); —R^(XC2) is —H; —R^(XCC) isindependently —F, —Cl, or —R^(XCCC); and —R^(XCCC) is independently -Meor -Et.
 45. A compound according to claim 33, wherein: the leadingphenylene group:

is:

—R^(XC1) is independently —H or —R^(XCC); —R^(XC2) is —H; —R^(XCC) isindependently —F, —Cl, or —R^(XCCC); —R^(XCCC) is independently -Me or-Et.
 46. A compound according to claim 34, wherein: the leadingphenylene group:

is:

—R^(XC1) is independently —H or —R^(XCC); —R^(XC2) is —H; —R^(XCC) isindependently —F, —Cl, or —R^(XCCC); and —R^(XCCC) is independently -Meor -Et.
 47. A compound according to claim 1, which is a compound of thefollowing formula or a pharmaceutically acceptable salt thereof:


48. A pharmaceutical composition comprising a compound according toclaim 47 and a pharmaceutically acceptable carrier, diluent, orexcipient.